3-Pyridyl enantiomers and their use as analgesics

ABSTRACT

The present invention relates to a method of controlling pain in mammals, including humans, comprising administering to a mammal or patient in need of treatment thereof selected compounds of formula I: ##STR1## or a pharmaceutically acceptable salt thereof. The invention further relates to selected (R) and (S) compounds of formula I above which are useful as analgesics as well as neuronal cell death preventors and anti-inflammatories.

This application is a conversion of U.S. Provisional Patent ApplicationSer. No. 60/032,321, filed Dec. 10, 1996.

FIELD OF THE INVENTION

The present invention relates to certain (R) and (S)-enantiomers of aclass of substituted 3-pyridyloxy alkylene azetidin-2-yl compoundshaving significant activity as analgesics. In addition, some(R)-enantiomers have a surprisingly improved toxicity profile over thecorresponding (S)-enantiomer of the same species. In addition to havingactivity as analgesics, the compounds are also effective in preventingneuronal cell death and are effective in treating or preventinginflammation.

BACKGROUND OF THE INVENTION

The search for more potent and more effective pain controllers oranalgesics continues to be a significant research goal in the medicalcommunity. A substantial number of medical disorders and conditionsproduce pain as part of the disorder or condition. Relief of this painis a major aspect of ameliorating or treating the overall disease orcondition. Pain and the possible allievation thereof is alsoattributable to the individual patient's mental condition and physicalcondition. One pain reliever, or a class, may not be effective for aparticular patient, or group of patients, which leads to a need forfinding additional compounds or pharmaceuticals which are effectiveanalgesics. Opioid and non-opioid drugs are the two major classes ofanalgesics (Dray, A. and Urban, L., Ann. Rev. Pharmacol. Toxicol., 36:253-280, 1996). Opioids, such as morphine, act at opioid receptors inthe brain to block transmission of the pain signals in the brain andspinal cord (Chemey, N. I., Drug, 51:713-737, 1996). Opioids such asmorphine have abuse and addiction liability. Non-opioids such asnon-steroid anti-inflammatory agents (NSAIDs) typically, but notexclusively, block the production of prostaglandins to preventsensitization of nerve endings that facilitate the pain signal to thebrain (Dray, et al, , Trends in Phannacol. Sci., 15: 190-197, 1994.;Carty, T. J. and Marfat, A., "COX-2 Inhibitors. Potential for reducingNSAID side-effects in treating inflammatory diseases", In: EmergingDrugs: Prospect for Improved Medicines. (W. C. Bowman, J. D. Fitzgerald,and J. B. Taylor, eds.), Ashley Publications Ltd., London, Chap. 19.,pp. 391411). Most of the commonly prescribed or over-the-counter (OTC)NSAIDs are also commonly associated with at one side effect or another,such as stomach ulceration or pain. For example, NSAIDs such as aspirinare also known to cause irritation and ulceration of the stomach andduodenum.

WO 94/08922 describes pyridyl ether compounds which enhance cognitivefunction. U.S. patent applications Ser. Nos. 08/474,873 and 08/485,537describe certain substituted pyridyl ether compounds as well as othercompounds which also act at the nicotinic acetylcholine receptor tostimulate or inhibit neurotransmitter release. WO 96/31475 describescertain 3-substituted pyridine derivatives which are described as beinguseful for a variety of disorders as modulators of acetylcholinereceptors. While some of these references have alluded to pain controlas a potential use of the compounds or analogs recited therein, theApplicants have discovered that a certain narrow class of compounds offormula I shown below have a surprising and unexpected very effectiveanalgesic effect. The Applicants have also found that activity at thenicotinic acetylcholine receptor site (e.g., binding thereto) is notnecessarily correlated with a compound's effectiveness as an analgesic,since some of the compounds having very high binding affinity areineffective as analgesics. The applicants have further found that some(R)-enantiomer in this series are particularly attractive because of anenhanced safety profile relative to the (S)-enantiomer. The Applicantshave also found that the claimed azetidinyl substituted 3-pyridylmethylene ether compounds have enhanced activity over the non-azetidinylclass of known compounds in the treatment of pain as well as theprevention of neuronal cell death and inflammation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows that the compound of Example 4 as the (R)-enantiomerprotects against SP-induced neurotoxicity in rat spinal cord cultures ina concentration dependent manner.

FIG. 2 shows that the compound of Example 4 when coadministered at asmall dose (0.2 umol/kg,i.p.) with varying doses of morphine (0-21umol/kg,i.p.) produced effective antinociceptive effects in the MouseHot Plate Paradigm.

FIG. 3 shows the antiallodynic effect of the compound of Example 4 inthe Chung Model of Neuropathic Pain. Light Bars reflect responses beforeadministration of the test compound (Ex. 4). Dark Bars representresponses 15 minutes following administration of the test compound. Thecompound of Ex. 4 is compared to saline.

FIG. 4 shows the antiallodynic effect of morphine during and followingrepeated administration of 21 umol/kg,i.p., compared with the responsefollowing repeated administration of saline.

FIG. 5 shows that the compound of Ex. 4 produced significantantinociceptive effects in the Formalin Model of Persistent Painrelative to saline (control) and that an increase in dosage diminishedthe nociceptive responses. The range of administration in this test was0.1-0.3 umol/kg,p.o. (oral administration).

FIG. 6 shows the antiinflammatory effects of the compound of Example 4in the carrageenan paw edema model wherein the compound is shown aseffective as dexamethansone at the dosage shown (panel A). FIG. 6 alsoshows that the nicotinic antagonist, mecaamylamine, prevents this effectshown by the compound of Ex. 4 in this model.

SUMMARY OF THE INVENTION

The present invention relates to a method of controlling pain inmammals, including humans, comprising administering to a mammal orpatient in need of treatment thereof a compound of formula I: ##STR2##or a pharmaceutically acceptable salt thereof, wherein R is selectedfrom H, or a prodrug derivative;

Z is selected from H, F or Cl;

X is selected from H, F, Br, Cl, CN, CHF₂, OMe, CH₂ F, or C₁₋₂ alkyl;and

Y is selected from H, F, Cl, Br, C₁₋₆ alkyl, vinyl, ethynyl, 3-propenyl,NO₂ or OC₁₋₂ alkyl.

In a preferred embodiment, the compound administered has formula IA:##STR3## or a pharmaceutically acceptable salt thereof, wherein R isselected from H, or a prodrug derivative;

Z is selected from H, F or Cl;

X is selected from H, F, Br, Cl, CN, CHF₂, OMe, CH₂ F, or C₁₋₂ alkyl;and

Y is selected from H, F, Cl, Br, C₁₋₆ alkyl, vinyl, ethynyl, 3-propenyl,NO₂ or OC₁₋₂ alkyl.

The present invention also relates to a method of treating orcontrolling pain in a patient in need of treatment thereof, comprisingadministering a compound or pharmaceutically acceptable salt of formulaI with the variables as recited above wherein the compound is the(S)-enantiomer at the chiral center at position 2 of the azetidine ring.Conversely, the invention also relates to a method of treating orcontrolling pain in a patient in need of treatment thereof, comprisingadministering the corresponding (R)-enantiomer, wherein X is selectedfrom the group consisting of F and Cl; and Y is H, wherein the(R)-enantiomeric compound of formula II has an improved safety profileover the (S)-enantiomer of the same species.

The present invention also relates to a method of treating paincomprising coadministering a compound of Formula I with an opiatenarcotic such as morphine wherein the combined regime more effectivelytreats pain and has a significant antinociceptive effect. The presentinvention relates to a method of treating or preventing pain in humansor animals comprising administering a dosage of about 0.2 umol/kg,i.p.of a compound of formula I with a dosage of morphine of about 2.6 to 21umol/kg,i.p. to a patient in need of treatment thereof. The compounds ofthe invention may be coadministered with other known safe and effectivenarcotic pain relievers which are well known to those of skill in thepain relieving arts and such coadministration is included within thescope of the methods herein.

The present invention also relates to novel compounds which areeffective nicotinic acetylcholine receptor modulators and effective paincontrollers wherein said compounds are chosen from a compound of formulaIA or a pharmaceutically acceptable salt thereof, wherein Z, Y, X andthe 2-azetidine stereochemistry are, respectively, selected from thegroup consisting of:

H, H, Me (S);

H, H, Me (R);

H, H, CN (S);

H, H, Cl (S);

H, H, Cl (R);

H, H, Br (R);

H, H, F (S);

H, H, F (R);

H, H, CHF₂ (S);

H, H, OMe (R);

H, Me, Cl (S);

H, Me, Cl (R);

H, Et, F (S);

H, ethenyl, Cl (S);

H, ethenyl, Cl (R);

H, ethenyl, F (S);

H, ethenyl, F (R);

H, ethynyl, Cl (S);

H, ethynyl, Cl (R);

H, Cl, Cl (S);

H, Cl, Cl (R);

H, Cl, F (S);

H, Br, Me (S);

H, Br, Me (R);

H, Br, Cl (S);

H, Br, Cl (R);

H, Br, F (S);

H, Br, F (R);

H, Me, H (R);

H, n-Pr, H (S);

H, ethenyl, H (S);

H, ethenyl, H (R);

H, 3-propenyl, H (S);

H, Cl, H (R);

H, F, H (S);

H, NO₂, H (S);

H, OEt, H (S);

Cl, H, H (S);

Cl, H, H (R);

F, H, H (S);

F, H, F (S);

F, H, Me (S); and

F, H, Me (R).

The preferred compounds are those that are effective as analgesics,neuronal cell death modifiers, or anti-inflammatories.

The present invention also relates to pharmaceutical compositionscomprising a compound of formula I with the variables R, X, Y, Z and thestereochemistry as described above and a pharmaceutically acceptableexcipient or diluent and to dosage forms containing such a composition.The invention further relates to a process for producing compounds offormula I which is further described below and to key intermediatesutilized in such process.

The present invention also relates to prodrug derivatives having formulaI wherein R is selected from the group consisting of alkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, amidomethyl, optionally substitutedvinyl and carbamyl. Acyl can encompass a variety of substituentsincluding an optionally derivatized amino acid attached to the nitrogenthrough an amide linkage.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of treating or controllingpain comprising administering a pharmaceutically effective amount of acompound of formula I with the variables Z, X and Y as defined above toa patient in need of treatment thereof. The invention also relates tocertain compounds and pharmaceutical compositions. For purposes of thisinvention, the terms recited in the claims are defined below:

A "patient in need of treatment thereof" is broadly defined to mean ahuman or veterinary animal patient in need of a pain reliever oranalgesic to diminish or control the feelings of pain associated with atemporary(acute) or chronic medical condition or disorder.

A "pharmaceutically acceptable salt" is defined to mean those salts,which are, with the scope of sound medical judgement, suitable for usein contact with tissues of humans and animals without undue toxicity,irration, allergic response and the like, and are effective for theirintended use as pain modulators, neuronal cell death modulators orantiinflammatories. Pharmaceutically acceptable salts are well known inthe art. See, for example, S. M. Berge, et al., in J. Pharm. Sci.,66:1-19 (1977). The salts may be prepared in situ during the finalisolation and purification of the compounds of formula I-III orseparately by reacting the free base function with a suitable organicacid. Representative acid addition salts include tosylate, benzoate,naphthalenesulfonate, hydrochloride, hydrobromide, sulfate, bisulfate,acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,borate, benzoate, lactate, phosphate, toluenesulfonate,methanesulfonate, naphthalenesulfonate, citrate, malate, fumarate,succinate, tartrate, ascorbate, glucoheptonate, lactobionate, laurylsulfate salts and the like. The preferred salt is the tosylate salt. Theinventors have found that the tosylate salt is less hygroscopic, morecrystalline, more stable, has a higher melting point, and is morereadily purified than the other salts. In addition, the tosylate salt isbetter suited for pharmaceutical formulation.

A "prodrug" or "pharmaceutically acceptable prodrug" is defined to meana compound that is rapidly transformed in vivo to yield a parentcompound, as for example, by hydrolysis in blood and during delivery ofthe compound per se to the pharmacological site of action. T. Higuchiand V. Stella provide a thorough discussion of the prodrug concept inProdrugs as Novel Delivery Systems, vol. 14 of the A.C.S. SymposiumSeries, A.C.S. (1975). Such prodrugs are included within the scope ofthe method of use herein. Examples of pro-drugs include pharmaceuticallyacceptable nontoxic derivatives of the azetidine nitrogen, includingamnides derived from C₁ -C₆ -alkyl carboxylic acids wherein the alkylchain is straight or branched or from aromatic acids such as derivativesof benzoic acid. These may be prepared by conventional methods. Theamides can also be derived from amino acids. Other prodrugs includealkyl derivatives and carbamate derivatives of the azetidine nitrogen.Specific examples of prodrug moieties are exemplified below.

The inventors have discovered that prodrugs of formula I, wherein R isnot H, will cleave in vivo to the compound of formula I, wherein R is H.As an example, it has been demonstrated that metabolic dealkylation ofN-alkyl azetidines occurs in vivo. Thus, analysis of samples of animalblood obtained over an eight hour period following IP injection of 1.9μmol/kg of the N-methyl compound of example 98 indicated thatsubstantial dealkylation to the N--H analog, example 8, occurs within 15minutes. The resulting plasma levels of the compound of example 8 are inthe range afforded by an effective IP dose of the compound, suggestingthat the analgesic effect of the its N-methyl prodrug is due to itsconversion in vivo to the active N--H form. Based on area under thecurve measurements, a conversion efficiency of 16% is estimated for theN-methyl compound. Similarly, IP administration of the N-ethyl (example99) or N-propyl (example 100) analogs to rat leads to in vivo conversionto the compound of example 8, with improved efficiencies (54% forN-ethyl, 30% for N-propyl) compared to the N-methyl analog.

Additional prodrugs that show analgesic effect are compounds of formulaI, wherein R, Z, Y, X and the 2-azetidine stereochemistry are,respectively, as follows:

methyl, H H, Cl, H, (S),

methyl, H, H, F, (S),

methyl, H, Br, Cl, (S),

methyl, H, H, Cl, (R),

methyl, H, Br, Cl, (R),

methyl, H, 3-propenyl, Cl, (S),

methyl, H, methyl, Cl, (S),

methyl, H, F, H, (R),

Boc, H, H, Cl, (R),

methyl, H, ethyl, F, (R),

ethyl, H, H, Cl, (R),

methyl, H, H, CH₂ F, (S),

methyl, H, methyl, Cl, (R),

ethyl, H, H, methyl, (S),

methyl, H, methyl, ethyl, (S),

methyl, H, Cl, F, (S),

cyclohexylmethyl, H, H, F, (R),

t-pentyl, H, H, Cl, (R),

3-methylbutyn-3-yl, H, H, Cl, (R),

ethyl, H, H, methyl, (R),

methyl, H, methoxy, H, (S),

t-butyl, H, H, methyl, (S),

A "pharmaceutically acceptable carrier or diluent" means a non-toxic,inert solid, semi-solid or liquid filler, diluent, encapsulatingmaterial or formulation auxiliarly of any type. Some of the examplesinclude sugars, such as lactose, glucose and sucrose; starches such ascorn starch and potato starch; celulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin, talc; alginate gums; excipients suchas cocoa butter and suppository waxes or other waxes; oils such aspeanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, cornoil and soybean oil; glycols, such as propylene glycol; polyols such asglycerin, sorbitol, mannitol and polyethylene glycol; esters such asethyl oleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffersolutions, as well as other non-toxic compatible substances used inpharmaceutical formulations. Wetting agents, emulsifiers and lubricantssuch as sodium lauryl sulfate and magnesium stearate, as well ascoloring agents, releasing agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants may also be presentin the composition, according to the judgement of the formulator.Examples of pharmaceutically acceptable antioxidants include watersoluble antioxidants such as ascorbic acid, cysteine hydrochloride,sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like.Oil soluble antioxidants and metal chelators may also be used.

A "therapeutically effective amount" of the analgesic agent is meant asufficient amount of the compound to treat pain to obtain the desiredtherapeutic response. It also means the amount necessary to inhibitneuronal cell death in the conditions associated with central andperipheral neuropathic pain which may include but are not limited toAIDS, cancer, stroke, Parkinson's disease, diabetes, osteoarthritis,tissue trauma, surgical intervention, and postherpetic neuralgia or toalleviate, reduce or prevent inflammation at the targeted site. It isunderstood that the total daily dosage or usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgement. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the symptoms of pain or discomfort; the activity ofthe specific compound employed and the specific composition as well asthe age, body weight, general health, sex and diet of the patient inneed of treatment thereof. Other factors include the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of treatment; drugs used incombination or coincidentally with the specific compound employed andthe like. Total daily dose of the compounds of the inventionadministered to a patient or animal in single or divided doses invarious forms or routes of administration may range from amounts ofabout 0.001 to 100 mg/kg body weight daily and preferrably 0.01 to 10mg/kg/day. Of course, this amount may vary depending upon the potency ofthe specific compound or drug wherein such ranges may vary accordinglyto fall below the 0.001 mg/kg/body weight daily. Dosage unitcompositions may contain such amounts or submultiples thereof to make upthe total daily dose.

The term "C₁ -C₆ -alkyl" means straight or branched chain versions ofmethyl, ethyl, propyl, butyl, pentyl or hexyl.

The markush structures or other variables as described above or in theclaims are self-explanatory and are standard chemical nomenclature orsymbology. The 2-position of the azetidine ring is a chiral center.

The term "improved safety profile" means that an enantiomes of theinvention typically elicited a lower response in the activation ofperipheral ganglionic nicotinic acetylcholine receptors which, ifoccurring in vivo, could be associated with undesired side effects onthe autonomic nervous (e.g. cardiovascular and gastrointestinal)systems. The safety profile is further supported by tabular data in thespecification. Moreover, one (R)-enantiomer can be shown to have12.8-fold less affinity at the skeletal muscle subtype of nicotinicacetylcholine receptor which, if occurring in vivo, could be associatedwith undesirable side effects with respect to muscle coordination andtone.

The term "effective nicotinic acetylcholine receptor binder" means thatthe compound has a binding affinity (Ki) in in vitro screens in at leastmicromolar (μM) range. The preferred binding affinity is in thenanomolar or picomolar range.

"Nitrogen protecting groups `P`" are chosen from those protecting groupscommonly known to protect nitrogen to enable chemical modification ormanipulation at another molecular site on the molecule. Such groups aredefined, for example, in the textbook by Stuart Warren OrganicSynthesis, The Disconnection Approach, pp 68-69,(1982) and in amultitude of standard well known organic chemistry texts.

"Leaving groups `L`" are chosen from those leaving groups well known inthe art which are readily displaced by the desired nucleophile to formcompounds of the invention. Tosylate is specifically utilized herein butany anionic leaving group commonly utilized for this purpose may also beutilized. Such groups are defined in Stuart Warren's reference above aswell as standard organic treatises.

As indicated above, the present invention includes compounds of theinvention and pharmaceutically acceptable excipients or diluents to formpharmaceutical compositions. Compositions suitable for parenteralinjection may comprise pharmaceutically acceptable sterile aqueous ornon-aqueous solutions, dispersions, suspensions or emulstions andsterile powders for reconstitution into sterile injectable solutions ordispersions. Examples of suitable aqueous and non-aqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols(propylene glycol, polyethylene glycol, gylcerol, and the like),suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity may bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. Prevention of the action ofmicroorganisms may be ensured by varous antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid andthe like. It may also be desirable to include isotonic agents, forexample, sugars, sodium chloride and other salts and the like. Prolongedabsorption of the injectable pharmaceutical form may be brought about bythe use of agents delaying absorption, for example, aluminummonostearate and gelatin. If necessary, the agents for the treatment ofpain or other conditions or indications described herein may beadministered intraveneously (IV) over the duration necessary toalleviate the discomfort of the patient and in the dosage that isdetermined to be best for the individual patient and the condition basedon sound medical judgement.

If desired, and for more effective distribution over a sustained periodof time, the compounds may be incorporated into slow-release ortargeted-delivery systems, such as polymer matrices, liposomes, andmicrospheres. They may be sterilized, for example, by filtration througha bacteria-retaining filter, or by incorporating sterilizing agents inthe form of sterile solid compositions, which may be dissolved insterile water, or some other sterile injectable medium immediatelybefore use.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound is admixed with at least one inert customary excipient(or carrier), such as sodium citrate or dicalcium phosphate, andadditionally (a) fillers or extenders, as for example, starches,lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, asfor example, carboxymethylcellulose, alginates, gelatine,polyvinylpyrrolidone, sucrose and acacia; (c) humectants, as forexample, glycerol; (d) disintegrating agents, such as, agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certaincomplex solicates and sodium carbonate; (e) solution retarders, such as,paraffin; (f) absorption accelators, such as, quaternary ammoniumcompounds; (g) wetting agents, such as, cetyl alcohol and glyerolmonostearate; (h) adsorbents, such as, kaolin and bentonite; and (i)lubricants, such as, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate or mixtures thereof. In thecase of capsules, tablets and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills andgranules may be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may contain pacifyingagents, and may also be of such composition that they release the activecompound in a certain part of the intestinal tract in a delayed manner.Examples of embedding compositions which may be used are polymericsubstances and waxes. The active compounds may also be microencapsulatedwith one or more of the above mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixers. Inaddition to the active compounds, the liquid dosage forms for oraladministration may also contain inert diluents commonly used in the art,such as water or other solvents suitable for injestion, solubilizingagents and emulsifiers, such as, ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils, in particular,cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil andsesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan or mixtures of these substances andthe like.

Besides such inert diluents, these liquid dosage forms may also includeadjuvants, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents. Suspensions, in addition tothe active compounds, may contain suspending agents, such as,ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitanesters, microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar and tragacanth, or mixture of these substances and the like.Compositions for rectal or vaginal administration may also be formulatedwith the appropriate known carriers such as cocoa butter or suppositorywaxes or other substances which are solid at ordinary room temperaturesbut liquid at body temperature which permits release of the drug in thismanner.

Dosage forms for topical or transdermal administration of a compound ofthis invention further include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalents or transdermal patches. If atransdermal patch is utilized, the active component may be admixed understerile conditions with a pharmaceutically acceptable carrier and anyneeded preservative, buffer or propellants as necessary. Compounds whichabsorb rapidly through the skin may need a formulation with absorptionretarding agents or barriers. Ophthalmic formulations, eye ointments,powders and solutions are also contemplated.

The compounds of the invention may also be delivered in the form ofliposomes which are known to be derived from phospholipids or otherlipid substances. Liposomes are formed by mono- or multi-lamellarhydrated liquid crystals that are dispersed in an aqueous medium. Anynon-toxic, physiologically acceptable and metabolizable lipid capable offorming liposomes may be used. The liposome formulation may also containother suitable excipients such as stabilizers, preservatives, excipientsand the like. Phospholipids or lecithins are generally preferred.Prescott, ed., Methods in Cell Biology, vol. XIV, Academic Press, NewYork, N.Y. (1976) describes methods to form liposomes.

The compounds of the invention may also be coadministered with aperipherally acting anti-cholinergic agent such as N-methylscopolamine,N-methylatropine, propantheline, methantheline, glycopyrrolate,trimethaphan, pentolinium, mecamylamine or pempidine provided that theadditional compounds do not affect the pain modulating or other targetedeffect of the active ingredient. In addition, the compounds of theinvention may be coadministered with opiate narcotics or pain relieverssuch as morphine wherein Applicants have shown that an improved painrelieving effect relative to morphine alone occurs when small doses ofthe compounds of the invention are administered with opiates such asmorphine. This "improvement" occurs at doses of compound which arenormally less effective in treating pain (e.g. 0.2 umol/kg,i.p. or less)with an increasing amount of morphine and may also occur at higher dosesof the compounds of the invention with morphine. In addition or as analternative to coadministration with morphine, coadministration may alsooccur with any known pain reliever or antiinflammatory as long as thereare no contraindications or diminishment in pain treatment or relief.This coadministration thus includes combinations of the compounds of theinvention and NSAIDS (including ibuprofen, (S)-ibuprofen, ibuprofensalts etc.).

Scheme 1 exemplifies the preparation of compounds of the invention,where P is a nitrogen protecting group such as Boc, Cbz, arylsubstituted Cbz, trifluoroacetyl, benzenesulfonyl, aryl substitutedbenzensulfonyl and others commonly known in the art (see T. W. Greeneand P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition,John Wiley & Sons, New York (1991); X is as defined above; in Scheme 1 Ris Y, as defined above, or a group convertible to Y, in a mannerdescribed below wherein, for example, a halogen at the Y position isreplaced in one or more steps with a C₁ -C₆ -alkyl, vinyl, propynyl orethynyl group; * indicates a chiral center which may be R or S,depending on the starting material; and HA is an acid which will readilyform a pharmaceutically acceptable salt with an amine, such astoluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid,hydrogen chloride, benzoic acid, citric acid, or tartaric acid. ##STR4##

In Scheme 1, the ether forming reaction may be accomplished by variousmethods, for example: 1) (a) by conversion of the hydroxyl group ofazetidine alcohol 1 to a leaving group by treatment with toluenesulfonylchloride, methanesulfonyl chloride, or trifluoromethanesulfonicanhydride or the like in an inert solvent such as THF, dimethylformamideor dichloromethane in the presence of a base such as triethylamine orpyridine or the like; or alternatively, conducting the reaction in neatpyridine; (b) followed by treatment with a pyridinol of structure 2under conditions sufficiently basic to cause removal of the phenolicproton of 2, for example with potassium hydroxide or sodium hydroxide inDMF, at a temperature from about 23° C. to about 120° C. as necessary toeffect a convenient rate of reaction; alternatively, a salt of 2,preferably a potassium or cesium salt, can be pre-formed by treatment of2 with potassium hydroxide or cesium hydroxide in a suitable solventsuch as methanol, which can be evaporated and replaced with a solventsuitable for the coupling reaction as described above; (2) the etherforming reaction also may be accomplished by treatment of the reactantswith a phosphine such as triphenylphosphine or tributylphosphine and anazodicarboxylate derivative, such as diethyl azodicarboxylate,di-tert-butyl azodicarboxylate, or 1,1'-(azodicarbonyl)dipiperidine in asuitable solvent, such as THF, benzene, or toluene or the like at atemperature of from about 0° C. to about 40° C. (the Mitsunobu reaction:see Hughes, Organic Reactions, 42, 335, 1992; Abreo, et al., J. Med.Chem. 1996, 39, 817).

One preferred coupling begins by cooling an isopropyl acetate solutionof the Boc protected alcohol 1 to about 5° C. Triethylamine is added.Mesyl chloride is then added at a rate to keep the temperature belowabout 10° C. Then the solution is stirred for about 15 minutes andwarmed to room temperature and stirred for another 4.5 hrs. An 8% sodiumbicarbonate solution was added. The mesylated alcohol was isolated,dissolved in DMF and treated with sodium hydroxide the appropriatehydroxypyridine. The solution is heated to about 80° C. for about 6 hrsto form compound 3. Compound 3 is isolated, dissolved in ethanol andthen deprotected with tosic acid at reflux temperature for 2 hrs to formthe corresponding compound 4 as the tosylate salt.

The precise conditions of N-deprotection depend on the nature of theprotecting group P, and are well described in suitable referencesources, such as Greene and Wuts (op. cit.) or computer databases suchas the Synopsys Protecting Groups Database (Synopsys Scientific Systems,LTD., Leeds, UK). Conveniently, for P=Boc, the deprotection is effectedby treatment of compound 3 with suitable mixtures (e.g. 1:1) oftrifluoroacetic acid and dichloromethane, or with hydrogen chloride inan ether or alcohol solvent; for P=Cbz, by hydrogenolysis (H₂ gas, Pdcatalyst, in an alcohol solvent such as methanol or ethanol, or othersolvent such as ethyl acetate in which the starting material issoluble), or with trimethylsilyl iodide, optionally formed in situ bymethods well known in the art, in a halocarbon solvent such aschloroform; for P=trifluoroacetyl, by treatment of 3 with a nucleophilesuch as a metal hydroxide, aqueous ammonia; or sodium borohydride; forP=arylsulfonyl, by treatment of 3 with sodium in liquid ammonia, or withsodium naphthalenide in an ether solvent such as dimethoxyethane, orwith sodium amalgam in an alcohol solvent such as methanol, or byelectrolysis.

The salt formation step consists of first isolating the free base of 4,for example, by extraction from an aqueous alkaline solution into anorganic solvent, for example diethyl ether, dichloromethane, or ethylacetate; drying the organic solvent with a suitable drying agent, forexample sodium sulfate or magnesium sulfate; optionally removing thesolvent and replacement with an alternative suitable solvent such asdiethyl ether, ethyl acetate, or ethanol; and treatment of the solutionwith an acid HA, selected from the group of pharmaceutically acceptablespecies, as exemplified above.

In Scheme 2, preparing enantiomerically pure (R)-azetidine alcohol 1(R=Cbz) from D-methionine is as described in Abreo, et al., op. cit.First, D-methionine in aqueous sodium hydroxide solution is treated withtosyl chloride to form N-tosyl-D-methionine, which is treated with MeIfollowed by 1N sodium hydroxide to affordα-(N-p-tosylamino)-γ-butyrolactone according to the method of Sugano andMiyoshi, Bull. Chem. Soc. Japan, 1973, 46, 669. Further conversion toazetidine-2-carboxylic acid is carried out by the procedure of Miyoshi,et al., Chem. Lett. 1973, 5-6. The lactone in ethanol is treated withgaseous HBr to form N-tosyl-g-bromonorvaline ethyl ester. The bromoesterin DMF solution with about four equivalents of H₂ O is treated with NaOHto form (R)-N-tosylazetidine-2-carboxylic acid (may be contaminated bythe (S)-enantiomer as determined by ¹ H-NMR analysis of the amidederivative with α-methylbenzylamine)(Abreo, et al., op. cit.) Treatingthe N-tosylazetidine-2-carboxylic acid with sodium in liquid ammoniaaffords azetidine-2-carboxylic acid, which is subsequently treated withN-(benzyloxycarbonyl)oxy succinimide according to Abreo, et al., toafford N-Cbz-azetidine-2-carboxylic acid. To remove contaminating(S)-enantiomer, the N-Cbz derivative in MeOH is treated with D-tyrosinehydrazide to form an insoluble salt of the (R)-enantiomer, which iscollected by filtration. The optical rotation of the subsequentlyliberated free acid is [α]_(D) =+105.4 (c 4.0, CHCl₃). Treating the freeacid with borane.THF affords 1 (R=Cbz). The S-enantiomer ((S)-1) may besynthesized analogously starting from L-methionine. If needed forenantiomeric enrichment, the product may be optically resolved withD-tyrosinehydrazide in analogy to the procedure described above. Otherprotecting groups, for example Boc, are readily incorporated by standardmethods, e.g. by reacting the intermediate or Cbz deprotectedazetidine-2-carboxylic acid with an appropriate standard reagent underprescribed conditions (Greene and Wuts, see above.). ##STR5##

Alternatively, in accordance with Scheme 3, racemicazetidine-(2)-carboxylic acid 5 may be prepared from γ-butyrolactoneaccording to Rodebaugh and Cromwell, J. Het. Chem., 1969, 6, 435. Theγ-butyrolactone is treated with bromine and catalytic phosphorus orphosphorus tribromide, then subsequently with benzyl alcohol and gaseoushydrogen chloride to afford benzyl α,γ-dibromobutyrate. The dibromide ina suitable solvent such as ethanol or acetonitrile is treated with oneequivalent of benzhydrylamine to afford benzylN-diphenylmethylazetidine-2-carboxylate. Hydrogenolysis over palladiumcatalyst, for example Pd(OH)₂ affords racemic 5. Resolution of thecorresponding N-Cbz derivative is conducted according to Rodebaugh andCromwell J. Het. Chem. 1969, 6, 993 to provide separately (R)- or(S)-N-Cbz-azetidine-2-carboxylic acid 6. Thus, treatment of a solutionof compound 5 in aqueous alkali with benzylchloroformate affords racemicN-Cbz-azetidine-2-carboxylic acid. Treatment of a methanol solution ofthe racemate with L-tyrosine hydrazide causes precipitation of theR-enantiomer as an insoluble salt, which is further processed asdescribed in the text accompanying Scheme 2. According to Rodebaugh andCromwell, J. Het. Chem., 1969, 6, 993, the pure (S)-enantiomer isobtained from the soluble fraction. ##STR6##

Alternatively, in accordance with Scheme 4, (R)-1 may be prepared by anovel process starting from (R)-azetidinone 7, which is prepared from adiester of D-aspartic acid according to Baldwin, et al., Tetrahedron1990, 46, 4733-48. Preferrably, excess RMgX consumes the triethylamineHCl salt formed during the desilylation. Thus, a solution of the freebase of dibenzyl D-aspartate in diethyl ether is treated withtrimethylsilyl chloride and triethylamine to afford an intermediateN-silyl derivative, which is treated with t-butylmagnesium chloride toafford 7. The trimethylsilyl group in this procedure may be replaced byalternative silyl groups e.g. a t-butyldimethylsilyl group asdemonstrated by Baldwin, et al., which is removable with fluoride ion.Treatment of 7 with an appropriate reducing agent, for examplediisobutylaluminum hydride (DIBAL), lithium aluminum hydride, aluminumhydride, mono- or dihalo aluminum hydride, or a mixture of aluminumtrichloride and lithium aluminum hydride in an ether solvent at -20° C.to 40° C. effects reduction both of the 2-carbobenzyloxy group tohydroxymethyl and the azetidinone carbonyl to methylene. The scope ofthis novel conversion is intended to include other esters, for exampleC1-C6 alkyl esters, and also to include, as appropriate, stepwisereduction of the ester group and the azetidinone carbonyl. Preferably,the benzyl ester is hydrogenolyzed to the free acid prior to reductionof the carbonyl moieties. For example, treatment of 7 with sodiumborohydride in methanol at room temperature according to Salzmann, et.al., (J. Am. Chem. Soc., 1980, 102, 6163-6165) or alternatively withlithium borohydride or calcium borohydride in ether or ether alcoholmixtures preferably at low temperature (-20° C. to 10° C.) affordsselective reduction of the ester group to afford the correspondingazetidin-2-one4-methanol (an alternative multistep route to thisintermediate in the (S)-enantiomeric series is disclosed in Tanner andSomfai, Tetrahedron Lett. 1987, 28, 1211-1214). Subsequent reduction ofthe azetidinone carbonyl with an appropriate reducing agent, for examplelithium aluminum hydride, aluminum hydride, mono- or dihalo aluminumhydride, or a mixture of aluminum trichloride and lithium aluminumhydride as described above provides the intermediateazetidine-2-methanol. Other methods of reducing the azetidinone carbonylmay be envisioned, e.g. conversion to a thioamide with P₂ S₅ orLawesson's reagent followed by reduction, for example, in the presenceof nickel. N-protection of the intermediate azetidine-2-methanol iscarried out using standard conditions, for example, treatment of theintermediate secondary amine with di-tert-butyl dicarbonate to affordthe product (R)-1 (P=Boc). The process from 7 to (R)-1 (R=Boc) has beendemonstrated in the case of a one-step reduction with lithium aluminumhydride in ether at 0° C. to ambient temperature with standard isolation(cf. Fieser and Fieser, Reagents for Organic Synthesis, vol. 1, p. 584)of the intermediate secondary amine followed by N-protection with Boc toproceed with a high degree of retention of chiral purity (>98% ee).Analogous to the preparation of (R)-1 starting from D-aspartic acid,(S)-1 may be prepared from L-aspartic acid. ##STR7## Methods forpreparation of various 5- and/or 6-substituted pyridin-3-ols 2 are asfollows:

Pyridin-3-ol (2, X=R=H) is commercially available (e.g. Aldrich).

6-Methylpyridin-3-ol (2, X=Me, R=H) is commercially available (e.g.Aldrich)

5-Chioropyridin-3-ol (2, X=H, R=Cl) is commercially available.

5,6-Dichloropyridin-3-ol (2, X=R=Cl) and 5-bromo-6-chloropyridin-3-ol(2, X=Cl, R=Br) are prepared from commercially available (Aldrich)2-hydroxy-5-nitropyridine according to Koch and Schnatterer, Synthesis,1990, 499-501. Thus, treatment of 2-hydroxy-5-nitropyridine with,respectively, either potassium chlorate or bromine affords therespective 2-hydroxy-3-halo-5-nitropyridines, which are treated withphosphorus oxychloride in the presence of quinoline to provide therespective 2-chloro-3-halo-5-nitropyridines. Treatment with iron or tinunder acidic conditions effects reduction of the nitro to afford therespective 5-amino-2-chloro-3-halopyridines. Diazotization of theintermediate with sodium nitrite in the presence of fluoroboric acid oralkyl nitrite in the presence of boron trifluoride affords anintermediate diazonium salt, which on heating with acetic anhydrideaffords the 5-acetoxy-2-chloro-3-halo-pyridine 8. A key step in theoverall sequence is the conversion of a 3-amino group to the 3-hydroxygroup under the conditions shown in Scheme 5. ##STR8## Scheme 5describes diazotization of 8 with alkyl nitrite in the presence of borontrifluoride etherate to afford an intermediate diazonium salt, which onheating with acetic anhydride affords the5-acetoxy-2-chloro-3-halo-pyridine 9. The diazonium intermediate mayalternately be prepared using sodium nitrite under acid conditions asdescribed in Koch and Schnatterer, Synthesis, 1990, 499-501. Hydrolysisor alcoholysis of the acetoxy group of 9 under mildly alkalineconditions affords 2 (X=Cl, R=Br or Cl).

6-Chloropyridin-3-ol (2, X=Cl, R=H) is prepared from commerciallyavailable 2-chloro-5-aminopyridine according to Effenberger, et al.,Chem. Ber., 1992, 125, 1131-1140, by treatment with sodium nitrite inthe presence of aqueous sulfuric acid followed by heating with aqueoussulfuric acid and isolation by extraction, or preferably by a modifiedroute according to the conditions shown in Scheme 5 where R=H.

5-Methyl-6-chloropyridin-3-ol is prepared from commercially available(Maybridge) 2-chloro-3-methyl-5-nitropyridine, by reduction of the nitrogroup (Fe, HOAc) followed by conditions analogous to those in Scheme 5.##STR9##

In accordance with Scheme 6 (above), 6-fluoropyridin-3-ol (2, X=F, R=H)and 6-fluoro-5-methylpyridin-3-ol (2, X=F, R=Me) are prepared from thecorresponding 3-amino compounds 11 under conditions analogous to thosein Scheme 5. Compound 11 is prepared by catalytic reduction of thecorresponding 3-nitropyridine derivative, which was prepared fromcommercially available 6-chloro derivative 10 according to Clark et al.,Tet. Lett. 1987, 28, 111-114. Thus, for example, a solution of 10 inacetonitrile is heated with potassium fluoride in the presence oftetraphenylammonium bromide to afford 11. ##STR10##

Intermediate 2 (from scheme 1) (X=H, R=F or Br) is prepared inaccordance with Scheme 7. Commercially available 3,5-dibromopyridine istreated with the anion of benzyl alcohol, for example, with sodiumbenzylate in DMF at room temperature, affords the monobenzyloxy compound12. Debenzylation of 12 by heating in 48% hydrogen bromide in aceticacid affords 2 (X=H, Y=Br). Treatment of a methanol solution of 12 withliquid ammonia followed by heating in a steel bomb at 120° C. to 150° C.for 16 to 48 hours in the presence of a copper salt, for example copper(I) bromide, affords compound 13. Treatment of 13 with an alkyl nitrite,for example, t-butyl nitrite in the presence of borontrifluorideetherate in an inert solvent such as methylene chloride affords anintermediate diazonium tetrafluoroborate, which is heated at 50° C. to90° C. in acetic anhydride, or preferably, in an inert solvent such astoluene to afford 3-benzyloxy-5-fluoropyridine. The benzyloxy compoundis stirred under a hydrogen atmosphere in the presence of a palladium(0) catalyst, for example 10% palladium on charcoal, in a suitablesolvent such as methanol, ethanol, or ethyl acetate at ambienttemperature to afford 2 (X=H, R=F). ##STR11##

Intermediate 2 (with X=F, R=Br) is prepared in accordance with Scheme 8.Compound 2 (X=H, R=Br), prepared as described in Scheme 7, is treatedwith an aryl diazonium salt, for example, commercially availablep-nitrophenyldiazonium tetrafluoroborate to afford the diazo coupledproduct 14. Diazo reduction by treatment with, for example, tin chlorideand hydrochloric acid in ethanol provides the intermediate2-amino-3-bromo-5-hydroxypyridine, which is diazotized, and treatedeither concurrently or subsequently with fluoride ion to afford thefluoro compound 2 (X=F, R=Br). For example, treatment of theintermediate 2-amino-3-bromo-5-hydroxypyridine with sodium nitrite inthe presence of HiF-pyridine at 0° C. to 70° C. affords 2 (X=F, R=Br).##STR12##

In accordance with Scheme 9, intermediate 2 (X=Me, R=Br) is preparedfrom 3-bromo-2-chloro-5-nitropyridine (V. Koch and S. Schnatterer,Synthesis, 1990, 499-501) in a manner analogous to that described byOdashima et al. (Bull. Chem. Soc. Japan, 1993, 66, 797-803). Thestarting material is treated with the sodium salt of diethylmalonatefollowed by hydrolysis and decarboxylation to replace the 2-chlorosubstituent with a methyl group. Thus, heating an intimate mixture of3-bromo-2-chloro-5-nitropyridine and diethyl sodiomalonate at 100° C.for about 1 hour, followed by heating the resultant mixture in thepresence of 12 N sulfuric acid at reflux for about 16 hours affords themethylated product. Reduction of the nitro group, for example with ironor tin under acidic conditions, for example, in the presence of aqueousacetic acid affords amino compound 15, which is converted to 2 (X=Me,R=Br) under conditions analogous to those in Scheme 5. ##STR13##

Additional compounds of the invention are prepared in accordance withScheme 10, where the starting materials 3 are prepared as described inScheme 1, using the appropriate pyridinol 2, obtained, in turn, asdescribed in Scheme 5 (for 2, X=Cl, R=Br); Scheme 7 (for 2, X=H, R=Br);Scheme 8 (for 2, X=F, R=Br); or Scheme 9 (for 2, X=Me, R=Br. The bromosubstituent is then replaced by a transition metal-catalyzedcross-coupling reaction, which may occur under a variety of conditionsdepending on the nature of Z. Treatment of a bromo compound 3 (R=Br;preferably X=H or Me) in THF with one to three equivalents ofmethylmagnesium bromide in diethyl ether in the presence of (dppp)NiCl₂at 40° C. to 70° C. affords 16 (Z=Me); when X=Cl or F, this method isless satisfactory than alternative methods disclosed in thisspecification. Treatment of a bromo compound 3 (R=Br) in toluene orbenzene with an excess of vinyltri-n-butyltin or allyltri-n-butyltin andcatalytic tetrakis(triphenylphosphine) palladium with heating at 80° C.to 110° C. affords compounds 16 (Z=vinyl or allyl). Treatment of a bromocompound 3 (R=Br) in toluene or benzene with an excess oftrimethylsilylacetylene or propyne and catalytictetrakis(triphenylphosphine) palladium in the presence of a copper salt,for example Cu(I)I, with heating at 80° C. to 110° C., optionally in asealed tube, affords compounds 16 (Z=trimethylsilylethynyl orpropyn-1-yl). Treatment of a bromo compound 3 (R=Br) in a nitrilesolvent, for example acetonitrile or propionitrile, with an excess of aC₄ -C₆ -alk-1-ene in the presence of a catalytic amount of a palladium(II) salt, for example, palladium (II) acetate, a triaryl phosphine, forexample tri-o-tolylphosphine, and a base, for example triethylamine, andheating, optionally in a sealed vessel, at 60° C. to 120° C. affordscompounds 16 (Z=C₄ -C₆ -alkenyl). Preparation of compounds 17 whereinY=ethynyl is accomplished by treatment of the corresponding compounds 16(Z=trimethylsilylethynyl) with an excess of potassium carbonate inmethanol at ambient temperature to 40° C. for from 1 to 24 hours.Preparation of compounds 17 wherein Y=C₂ -C₆ -alkyl is accomplished bystirring the corresponding compounds 16 (Z=vinyl, allyl, propynyl or C₄-C₆ -alkenyl) under a hydrogen atmosphere in the presence of a platinumcatalyst, for example, 5% platinum on charcoal, in a solvent such asmethanol, ethanol, or ethyl acetate. Compounds 17 or compounds 16 (Z=Y)are converted to compounds of the invention by deprotection and saltformation using a method selected from those described with Scheme 1,for example, treatment with 1:1 trifluoroacetic acid/methylene chloridefor N-deprotection of 16 or 17 (P=Boc).

As described above, the compounds of the invention are prepared from aprocess which comprises:

(1) contacting an azetidine of formula 1 wherein P is as recited abovewith a multisubstituted pyridyl compound of formula 2 with R and X asrecited above to form, upon coupling and deprotection, a compound offormula I or a precursor to a compound of formula I wherein Y is chosenfrom C₁ -C₆ -alkyl, vinyl or ethynyl.

The term "contacting" means exposing 1 or a modified version of 1 whichis selected from a compound of formula 1' ##STR14## wherein L is aleaving group exeplified by toluenesulfonate, methanesulfonate, ortrifluoromethanesulfonate, which is prepared by reacting compound 1 withtoluenesulfonyl chloride, methanesulfonyl chloride ortrifluoromethansulfonic anhydride in an inert solvent such as THF,dimethylformamide or dichloromethane in the presence of a base such astriethylamine or pyridine or in neat pyridine to a reactant selectedfrom the multisubstituted pyridyl compound 2 or a derivative thereofunder the conditions necessary to effect the coupling of 1 and 2 toresult in, upon deprotection, the product. The preferred reactionconditions are typically in solution.

A "derivative thereof" as specified directly above is selected from acompound of formula 2 wherein the phenolic proton is abstracted(removed) to leave a nucleophilic anion or is selected from a potassiumor cesium salt of a deprotonated derivative of formula 2. A derivativethereof is also selected from the Mitsunobu intermediate which isgenerated by exposing both compounds 1 and 2 to a phosphine such astriphenylphosphine or tributylphosphine and an azadicarboxylate such asdiethyl azodicarboxylate, di-tertbutyl azodicarboxylate or1,1'-(azodicarbonyl)dipiperidine in suitable solvents such as THF,benzene, or toluene at a temperature of from about 0 to about 40 degreesCelcius.

More particularly, the present invention relates to a process forproducing R-enantiomers which comprises,

(a) preparing a compound of formula 1 or a derivative 1' thereof with(R) stereochemistry at the 2-position on the azetidine ring;

(b) preparing a compound of formula 2 or a derivative 2' thereof;

(c) contacting the reactant formed in step (a) with the reactant formedin step (b) under suitable conditions to form a compound of formula 3;

(d) deprotecting the compound of formula 3 under suitable conditions toform the R-enantiomers.

Alternatively, steps (a')-(d') using the (S)-enantiomer in step (a) asabove may be performed to form a compound of formula I which is the(S)-enantiomer at the 2-position of the azetidine.

The invention also relates to a process as described above furthercomprising a step (e) (or (e') in the case of the (S)-enantiomer) ofadding an acid HA to the deprotected compound produced in step (d) (or(d')) to form a compound of formula 4 (or the (S)-enantiomer thereof inthe case of (e').

Biological Protocols

Compounds of the invention were subjected to in vitro assays against thenicotinic acetylcholine receptor as described below and were found to beeffective binders to the receptor. Functional in vitro assays were alsoperformed to assess the ability of the compounds to modulate nicotinicacetycholine receptor function related to ion flux, and neuroprotectiveactions. In addition, the compounds of the invention were assessed inknown pain or analgesic animal models which are utilized to bepredictive of analgesic properties in higher mammals, including humans,as well as antiinflammatory actions (Sheen, K. and Chung, J. M., BrainRes., 610:62-68, 1993. The relevance of animal neuropathy models forchronic pain in humans is described by Seltzer (Neurosciences, 7:211-220, 1995).

Compounds of the invention were found to be useful as nicotinicacetylcholine receptor binders and as effective analgesics. The testsdescribed below show that the compounds of the invention are effectivein animal models of pain. In addition to the compounds general analgesicproperties, generally, some (R)-enantiomers relative to the(S)-enantiomers of the same chemical formula has an improved safetyprofile which is demonstrated in two ways (peripheral side effectsrelated to activation of autonomic ganglionic-like receptors andperipheral side-effects related to activation of skeletal muscle-likenicotinic acetylcholine receptors). Data showing this improved safetyprofile are also presented below.

In Vitro Protocols

Protocol For Determination of Nicotinic Acetylcholine Channel ReceptorBinding Potencies of Ligands

Binding of [³ H]-cytisine ([³ H]-CYT) to neuronal nicotinicacetylcholine receptors was accomplished using crude synaptic membranepreparations from whole rat brain (Pabreza et al., Molecular Phannacol.,1990, 39:9). Washed membranes were stored at -80° C. prior to use.Frozen aliquots were slowly thawed and resuspended in 20 volumes ofbuffer (containing: 120 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 2 mM CaCl₂ and 50mM Tris-Cl, pH 7.4 @4° C.). After centrifuging at 20,000× g for 15minutes, the pellets were resuspended in 30 volumes of buffer.Homogenate (containing 125-150 μg protein) was added to triplicate tubescontaining concentrations of test compound and [³ H]-CYT (1.25 nM) in afinal volume of 500 μL. Samples were incubated for 60 minutes at 4° C.,then rapidly filtered through Whatman GF/B filters presoaked in 0.5%polyethyleneimine using 3×4 mL of ice-cold buffer. The filters arecounted in 4 mL of Ecolume® (ICN). Nonspecific binding was determined inthe presence of 10 μM (-)-nicotine and values were expressed as apercentage of total binding. IC₅₀ values were determined with the RS-1(BBN) nonlinear least squares curve-fitting program and IC₅₀ values wereconverted to Ki values using the Cheng and Prusoff correction (Ki=IC₅₀/(1+[ligand]/Kd of ligand). Alternately, data were expressed as apercentage of the total specific binding. The binding data (shown inTable 1) suggest that the compounds of the present invention have highaffinity for the neuronal nicotinic acetylcholine receptor.

                  TABLE 1                                                         ______________________________________                                                                          [3H]CYT                                       Ex. * X Y Ki (nM)                                                           ______________________________________                                         6        R      H         H      0.04                                           4 R Cl H 0.05                                                                 8 R F H 0.06                                                                  11 R H F 0.34                                                                 14 R H Me 0.18                                                                16 R Cl Cl 0.06                                                               18 R Cl Br 0.02                                                               97 * R H H 85                                                                114 R H Cl 0.12                                                               115 R Me H 0.07                                                               118 ** R Me H 4.8                                                             119 R OMe H 0.67                                                              124 R Me Br 0.03                                                              125 R F Br 0.04                                                               127 R Cl Me 0.06                                                              128 R Br H 0.17                                                               129 R F ethenyl 0.09                                                           7 S H H 0.04                                                                  19 S Cl H 0.04                                                                9 S F H 0.16                                                                  20 S Me H 0.06                                                                10 S H F 0.09                                                                 21 S H Cl 0.04                                                                12 S H Br 0.26                                                                13 S H Me 0.05                                                                23 S H Et 0.11                                                                24 S H n-Pr 0.05                                                              22 S H vinyl 0.97                                                             15 S Cl Cl 0.02                                                               17 S Cl Br 0.02                                                               25 S Cl Me 0.05                                                               27 S Cl Et 0.04                                                               28 S Cl n-Pr 0.03                                                             29 S Cl n-Bu 0.16                                                             26 S Cl vinyl 0.24                                                            30 S Cl ethynyl 0.04                                                          31 S F Br 0.03                                                                32 S F Me 0.10                                                                33 S F Cl 0.04                                                                34 S Me Br 0.02                                                               36 S Me Et 0.04                                                               35 S Me vinyl 0.22                                                           113 S CHF2 H 0.17                                                             116 ** S F H 0.34                                                             117 ** S Me H 0.17                                                            120 S H OEt 0.04                                                              121 * S H H 2.3                                                               122 ** S H H 0.10                                                             123 S CN H 1.9                                                                126 S F Et 0.07                                                               130 S H 3-propenyl 0.04                                                       131 S F ethenyl 0.13                                                          132 S H NO2 0.33                                                            ______________________________________                                         * compound also has a 2chloro substitutent                                    ** compound also has a 2fluoro substitutent                              

Tissue isolates from Torpedo californica electroplax model theproperties of nicotinic acetylcholine receptors at the mammalianneuromuscular junction receptor. For that reason, binding of compoundswas determined using a solid phase binding assay that measures thebinding of [¹²⁵ I] α-bungarotoxin (106 Ci/mmol) to tissue isolates. Thewells of a 96-well microtiter plate (Immulon Removawells Strips,Dynatech, Chantilly, Va.) were coated with 0.5 μg of Torpedo membranes(ABS Inc., Wilmington, Del.) in 50 mM NaHCO₃ buffer, pH 9.6, for 12hours at 4° C. Wells were then washed twice with phosphate bufferedsaline (PBS) and quenched for 1 hour with 5% bovine serum albumin (BSA).[¹²⁵ I α-bungarotoxin (˜1.9 nM/100 μL 10 mM phosphate buffer, pH7.4/0.2% BSA) was then added to the wells for 1 hour. For competitionexperiments, increasing concentrations of competitor (50 μL) were addedto wells in triplicate followed immediately by 50 μL of [¹²⁵ Iα-bungarotoxin and incubated for 1 hour. Non-specific binding wasdetermined in the presence of 1 μM α-bungarotoxin. After incubation,wells were washed 5 times with PBS. Individual wells were placed invials and radioactivity measured in a gamma counter (Model 5000,Beckman, Fullerton, Calif.).

The data in Table 2 demonstrate that the (R)-enantiomer of the compoundof Example 4 remarkably has 12.8-fold reduced affinity (i.e. enhancedselectivity) for the neuromuscular junction nicotinic acetylcholinereceptor, which contrasts with its equivalent activity at neuronalnicotinic acetylcholine receptors label by [³ H]-cytisine (Table 1).These data indicate that Example 4 would be safer and less likely tocause motoric or respiratory complications than its (S)-enantiomer.

                  TABLE 2                                                         ______________________________________                                                                       Ki (nM)                                          Ex. * X Y α-bungarotoxin                                              ______________________________________                                        19        S     Cl         H   1300                                             4 R Cl H 16,600                                                             ______________________________________                                    

Protocol for the Determination of Ability of Nicotinic AcetylcholineReceptor Ligands to Activate Peripheral Ganglionic Receptors

Cells of the IMR-32 human neuroblastoma clonal cell line (ATCC,Rockville, Md.) were maintained in a log phase of growth according toestablished procedures. Experimental cells were seeded at a density of500,000 cells/mL into a 24-well tissue culture dish. Plated cells wereallowed to proliferate for at least 48 hours before loading with 2μCi/mL of ⁸⁶ Rb⁺ (35 Ci/mmol) overnight at 37° C. The ⁸⁶ Rb⁺ effluxassays were performed according to previously published protocols(Lukas, R. J., J. Phamacol. Exp. Ther., 265, 294-302, 1993) exceptserum-free Dulbecco's Modified Eagle's Medium was used during the ⁸⁶ Rb⁺loading, rinsing, and agonist-induced efflux steps. Data reflect theactivation of ⁸⁶ Rb⁺ flux at a concentration of 1 μM, and reflect theresponse as a percentage of the maximum response elicited by(S)-nicotine. The data are interpreted such that the larger theresponse, the more potent is the activation of peripheral ganglionicreceptors, which is further interpreted to suggest that, in vivo, a morepotent contribution to undesired effects will occur, for example, on thecardiovasular and/or gastrointestinal systems.

The data for activation of ⁸⁶ Rb⁺ flux in the IMR-32 cell line forenantiomeric pairs of compounds of the invention are compared in Table3. The data show that in the large majority of cases (5 of 6 listed),the (R)-enantiomer of each pair is less potent to activate ⁸⁶ Rb⁺ flux.than the corresponding (S)-enantiomer. Therefore, it is expected thatthe (R)-enantiomers will be less potent to elicit undesired effects onperipheral autonomic nicotinic acetylcholine receptors of, for example,the cardiovascular or gastrointestinal systems.

                  TABLE 3                                                         ______________________________________                                                                          IMR-32                                            % maximal                                                                     nicotine                                                                      response at 1                                                                 μM Cmpd                                                                Example # * X Y conc'n                                                      ______________________________________                                        4            R     Cl         H   97                                            19 S Cl H 173                                                                 8 R F H 46                                                                    9 S F H 103                                                                   16 R Cl Cl 85                                                                 15 S Cl Cl 117                                                                18 R Cl Br 93                                                                 17 S Cl Br 120                                                                11 R H F 31                                                                   10 S H F 28                                                                   14 R H Me 15                                                                  13 S H Me 27                                                                ______________________________________                                    

Protocol for Determination of Effectiveness of Nicotinic AcetylcholineReceptor Ligands as Agents to Prevent Neuronal Cell Death in the SpinalCord

(-)-Nicotine, ABT418, ABT-089 and related nicotinic acetylcholinereceptor ligands have properties indicative of neuroprotection in vitroand in vivo (Akaike, A., et al., Brain Res., 644:181-187, 1994;Donnelly-Roberts et al., Brain Res., 729:36-44, 1996; Marin, P., et al.,Neuroreport, 5: 1977-1980, 1994; Martin, E. J., et al., Drug Dev. Res.,31:135-141, 1994; Shimohama, S., et al., Annals New York Academy ofSciences, 356-361, 1996).

The effect of the compound of Example 4 to protect against neurotoxicityin one model relevant to neuropathic pain and spinal cordneurodegeneration is detailed below.

Primary spinal cord of mixed large and small diameter motoneuroncultures were prepared from Sprague-Dawley rats at day 13 of gestationas described by Regan and Choi (J. Neuroscience, 43:585-591, 1991).Cells were plated onto poly-L-lysine coated 96 well culture dishes at adensity of about 50,000 cells per well in L15 medium containing 2% HorseSerum (HS)/33 mM glucose/2 mM glutamine/50 U/mL pen:strep/B27supplement/10 mg/mL NGF. To eliminate fibroblasts and Schwann cells fromthe spinal cord cultures, antimitotic feed medium (L15 plus 10 mMuridine and 10 MM 5-fluro-2'-exoxyuridine with no HS) is used at day 3for 2 days. Cultures were maintained at 36° C./10% CO₂.

After 7 days in vitro (DIV), cells were pretreated with test compounddiluted in L-15 medium with B27 supplement for 2 hours. Thispretreatment solution was replaced by HBSS (without magnesium, butcontaining 3 mM calcium chloride) containing substance P (SP) (30 μM) orglutamate (Glu) at 300 μM and co-applied with the test compound for anadditional 15 minutes. This compound/insult solution was removed andreplaced with fresh L-15/B27 media for 24 hours. Neuronal damage wasassessed by either 1) measuring the levels of the cytosolic enzymelactate dehydrogenase (LDH) released into the medium by the damagedcells or 2) staining the cells with 4% Trypan blue for 5 min andmorphologically assessing damage by light microscopy. LDH release wasquantified using a Cytotox 96 assay kit (Promega; Madison, Wis.) asdescribed previously (Donnelly-Roberts, op. cit.). Basal LDH release wastypically between 6-9% of the LDH released following lysis of the cellswith 0.8% Triton X-100, whereas insults usually resulted in a 2- to3-fold increase over basal levels. In order to be able to compare fromplate to plate, all values were normalized to the 30 μM SP-inducedmaximal LDH release (assigned 100%). These toxic events arereceptor-mediated, because the effect of SP can be blocked by the SPreceptor antagonist, spantide II (100 μM), and the Glu-induced toxicityblocked by the NMDA receptor antagonist, MK-801 (1 μM). However theseinduced toxicities are likely to be mechanistically distinct, sinceMK-801 cannot prevent SP-induced toxicity.

The results demonstrate that the compound of Example 4 has the potentialto be more effective than NMDA receptor antagonists against a broaderspectrum of neurotoxic events. In contrast to MK-801, compound ofExample 4 reduces both SP and Glu-induced neurotoxicity with an EC₅₀ forneuroprotection of 10 μM (FIG. 1). However, the (S)-enantiomer, compoundof Example 19, is 10-fold less potent as a neuroprotectant in spinalcord (EC₅₀ =100 mM). This neuroprotective effect is blocked by selectivenicotinic antagonists, mecamylamine (10 μM), methyllycaconitine, (MLA,10 nM) and α-bungarotoxin (α-BTX, 1 nM) indicating a neuronal nicotinicreceptor mechanism. These results suggest that compounds of formula Iare effective in a method of treating or preventing neuronal cell deathin mammals, including humans and thus are useful in the disordersassociated therewith in the conditions associated with central andperipheral neuropathic pain which include AIDS, cancer, stroke,Parkinson's disease, diabetes, osteoarthritis, tissue trauma, surgicalintervention or post-therapeutic neuralgia. The present invention thusincludes a method of treating neurotoxicity or spinal cordneurodegeneration comprising administering a therapeutically effectiveamount of a compound of formula I to a patient in need of treatmentthereof. The preferred compound is the R-enantiomer.

In vivo Protocols

Protocol for Determination of Effectiveness of Nicotinic AcetylcholineReceptor Ligands as Analgesic Agents in the Mouse Hot Plate Paradigm

Separate groups of mice (n=8/group) were utilized for each dose group.All drugs were administered by the intraperitoneal route ofadministration. Animals were dosed 30 minutes prior to testing in thehot-plate. The hot-plate utilized was an automated hot-plate analgesiamonitor (model # AHP16AN, Omnitech Electronics, Inc., Columbus, Ohio).The temperature of the hot-plate was maintained at 55° C. and a cut-offtime of 180 seconds was utilized. Latency until the tenth jump wasrecorded as the dependent measure. An increase in the tenth jump latencyrelative to the control was considered an antinociceptive effect. Table4 shows the minimally effective dose (MED), among the doses tested, atwhich a significant antinociceptive effect, as defined above, wasobserved for compounds of the invention. The data show that thecompounds of the invention generally show a significant antinociceptiveeffect at a dose between 0.062 to 62 μmol/kg, i.p.

Protocol for Determination of Effectiveness of Nicotinic AcetylcholineReceptor Ligands as Analgesic Agents in the Chung Model of NeuropathicPain

The Chung model of neuropathic pain is produced in rats (male,Sprague-Dawley) by unilateral ligation of L5 and L6 nerves whichinnervate the hindlimb (Kim and Chung, Pain 1992, 50, 355-363. Followinga sufficient recovery period, these animals show an apparent allodynic(withdrawal from a normally nonpainful stimulus) response to a tactilestimulus (i.e., VonFrey hairs). This response is quantitated bydetermining a 50% threshold response to different weight VonFrey hairs.The hairs are applied to the mid-plantar area of the hind pawipsilateral to the ligations. The animals were tested repeatedly overthe course of 120 min. A crossover design was used with each animalbeing tested after administration of saline and each dose of testcompound on separate days. A significant increase in the 50% treatmentwith test compound relative to the 50% threshold after treatment withsaline was considered an anti-allodynic effect.

An anti-allodynic effect is interpreted to demonstrate strong potentialfor the treatment of neuopathic pain. Selected compounds of theinvention were tested in this model of neuropathic pain with resultspresented in Table 4. The table shows the minimally effective dose(MED), among the doses tested, at which the selected compounds effecteda significant increase, relative to control subjects, in the 50%threshold response. The data indicate that seven out of the eightcompounds tested showed a significant effect at at least one of thetested doses, and that the observed significant effects occurred in thedose range 0.19 to 0.62 μmol/kg, i.p.

                  TABLE 4                                                         ______________________________________                                                                   MED       MED                                            Hot plate model Chung model                                               Ex. * X Y (μmol/kg, i.p.) (μmol/kg, i.p.)                             ______________________________________                                        6     R      H      H      NS                                                   4 R Cl H 0.62 0.3                                                             8 R F H 1.9 0.62                                                              11 R H F NS                                                                   14 R H Me 62                                                                  16 R Cl Cl 6.2 0.19                                                           18 R Cl Br 0.62                                                               7 S H H 6.2                                                                   19 S Cl H 0.62 0.3                                                            9 S F H 0.62                                                                  20 S Me H 0.62                                                                10 S H F 6.2 0.62                                                             21 S H Cl NS                                                                  12 S H Br NS                                                                  13 S H Me NS                                                                  23 S H Et NS                                                                  24 S H n-Pr 62                                                                15 S Cl Cl 1.9 NS                                                             17 S Cl Br 1.9 0.19                                                           25 S Cl Me 0.062                                                              27 S Cl Et NS                                                                 28 S Cl n-Pr NS                                                               29 S Cl n-Bu NS                                                               26 S Cl vinyl 1.9                                                             30 S Cl ethynyl 6.2                                                           31 S F Br 6.2                                                                 32 S F Me NS                                                                  34 S Me Br 0.62                                                               36 S Me Et NS                                                                 35 S Me vinyl NS                                                              122 S H H -- 1.9                                                              **                                                                          ______________________________________                                         NS = no significant effect observed relative to saline controls at the        doses tested.                                                                 ** compound also has a 2fluoro substitutent.                             

As shown in Table 4, some of the compounds in the (S) or (R) series didnot show activity in the analgesic models. A method of treating orpreventing pain, comprising administering a compound of formula I with Xand Y as recited previously expressly excludes those specific (S) or (R)compounds shown above which had no activity in the pain models.Compounds which do show activity or which may show activity in laterdeveloped models of pain are included within the scope of the methodclaim. The compounds of formula I also have activity as modifiers ofneuronal cell death and/or inflammation.

Protocol for Determination of Effectiveness of Nicotinic AcetylcholineReceptor Ligands in interfering with Locomotor Activity in the RotarodAppartus

Motor coordination was assessed using an accelerating rotarod apparatus(Omnitech Electronics, Inc., Columbus, Ohio). Locomotor activity wasmonitored under dim light in a 41×41 cm. open field using a photobeamactivity system (San Diego Instruments, San Diego, Calif.). The mousewas placed on a 3.5 cm diameter rod which increased in speed from 0 to40 rpm over 120 seconds. The time required for the mouse to fall fromthe rod was recorded with a maximum score of 120 seconds. Twenty-fivemin after receiving an i.p. injection, the mice were placed in the openfield for 5 min. After removal from the open field (i.e., 30 min afterinjection), they were immediately tested on the rotarod. Bodytemperature was assessed using a probe inserted 3 cm into the rectumapproximately 35 min after injection. (YSI Tele-Thermometer, YellowSprings Instrument Co., Inc., Yellow Springs, Ohio). Diazepam (10.5μmol/kg, i.p.) was used as a positive control.

The compound of Example 8 was tested in the activity, temperature androtarod test and showed no rotarod effect until a dose of 19 wasreached. In contrast, the compound of Example 9 showed impairments at0.62 μmol/kg in 2 of 3 experiments. This demonstrates that the(R)-enantiomer (Example 8) had fewer motor coordination side effectsthan the (S)-enantiomer (Example 9).

Protocol for Determination of Effectiveness of Nicotinic AcetylcholineReceptor Ligands as Analgesic Agents in Combination with Opioids in theMouse Hot Plate Paradigm

In this set of experiments a non-effective dose of the compound ofExample 4 was combined with subthreshold and effective doses ofmorphine. Compounds were co-mixed in a syringe, and co-administered viathe intraperitoneal route 30 min prior to testing in the mouse hot-plateparadigm as indicated above. Separate groups of animals (n=7-8/group)were used for each dose group.

The results in FIG. 2 demonstrate that the compound of Example 4combined with subthreshold doses of morphine can produce effectiveantinociceptive activity. In addition, combining non-effective doses ofcompound of Example 4 with effective doses of morphine results inenhanced antinociceptive activity.

Taken together, these results suggest that combination therapy ofcompounds disclosed within together with opioids may result inremarkably enhanced analgesic activity. It is conceivable thatcombination of these nicotinic acetylcholine ligands with otheravailable analgesics may also result in added beneficial effects.

Protocol for Determination of Effectiveness of Nicotinic AcetylcholineReceptor Ligands as Analgesic Agents in the Chung Model of NeuropathicPain Following Repeated Dosing

Animals were surgically prepared as described above for the Chung model.For assessment of each test compound, two treatment groups (6 animalseach) were established. One group was injected (i.p.) with test compoundtwice daily for 5 days, and the other group was injected on the sameschedule with saline. Responses to von Frey hairs were assessed asdescribed above both before, and 15 minutes after, injection on thefirst 2 days and also on the 5th day. The saline-treatment group wasgiven saline for the first 4 days and on the morning of the 5th day, butreceived a challenge of the test compound in the afternoon of the fifthday. The results for test compounds as the compound of Example 4 and formorphine are shown in FIGS. 3 and 4, respectively, wherein light barsreflect responses before administration of test compound, and dark barsrepresent responses fifteen minutes following administration of testcompound.

Significant anti-allodynic effects of compound of Example 4 wereobserved during each test session, and no differences in theanti-allodynic effects of this challenge with compound of Example 4 werenoted between rats previously given b.i.d. injections of compound ofExample 4 (0.3 μmol/kg, i.p) and rats previously given salineinjections. This result indicates that the anti-allodynic effect ofcompound of the compound of Example 4 does not decrease followingrepeated dosing. In contrast, the effects of morphine (21 μmol/kg) inthis model were significantly reduced after repeated b.i.d. dosing. Thisresult indicates that the compound of Example 4 may have greater utilitythan morphine in alleviating chronic, neuropathic pain.

Protocol for Determination of Effectiveness of Nicotinic AcetylcholineReceptor Ligands as Analgesic Agents in the Formalin Model of PersistentPain

The test follows the protocol established in the literature (Tj.oslashed.lsen, et aL, Pain, 1992, 51, 5-17). A 50 μL injection of 5%formalin, a potent chemical irritant, was made subcutaneously into thedorsal surface of one of the rear paws of male Sprague-Dawley rats.Rates of nociceptive behaviors (e.g., flinching, biting, licking, orelevating the paw) typically show a biphasic pattern over time, with abrief, initial period lasting about 5 min. following the formalininjection and a longer phase of responding beginning about 20 min. afterthe formalin injection. This second phase of responding is maximal atabout 30-50 minutes after injection and appears to involve aninflammatory component. Nociceptive behaviors were recorded during thissecond phase of responding (30-50 minutes after formalin injection)using a time-sampling procedure (15 sec. of observation time for eachrat during each minute). The test compound was administered orally to agroup of seven rats at varying doses 15 minutes prior to formalininjection. Responses are compared to a similar group receiving saline.

The results in FIG. 5 demonstrate that the compound of Example 4produced significant antinociceptive effects in this model of persistentpain after oral administration and indicate that this compound may haveutility as an oral analgesic for the treatment of acute pain.

Protocol for Determination of Effectiveness of Nicotinic AcetylcholineReceptor Ligands as Analgesic Agents in the Paw Thermal Stimulator(Hotbox) Model

For assessing nociceptive responses to an acute thermal stimulus, acommercially available paw thermal stimulator was utilized(Anesthesiology Research Laboratory, Department of Anesthesiology,University of California at San Diego, La Jolla, Calif.). This devicehas been previously described (Dirig, D. M. and Yaksh, T. L., Pain, 62:321-328, 1995) and is based on the initial work of Hargreaves et al.(Pain, 32: 77-88, 1988). Rats were placed in Plexiglas cubicles thatwere located on a glass surface of the apparatus. The surface of theglass was maintained at 30° C. A thermal stimulus was applied to thebottom of the rear foot of the rat via a movable focused projectionbulb. The stimulus current was maintained at 4.8 Amps. The latency untilthe animal moved its foot from the stimulus was recorded automaticallyby use of photodiode motion sensors. In the current studies, a 20 secondcut-off was employment to limit possible tissue damage followingexposure to the stimulus.

All studies began with a 20 min acclimation period. Following theacclimation period, a baseline measure was determined for each animal.Following determination of baseline, treatments were administered andmeasures were taken at various time points following treatment (e.g.,15, 30, and 45 min). For clarity, data were collapsed over time forstastical analysis (unless otherwise noted).

Stock solutions of compounds were prepared in absolute ethanol at aconcentration of 62 μmol/ml. From this, solutions were made with 10%ethanol, and dosed by injection i.p. Compounds were tested in the doserange of from 0.62 to 6.2 μmol/kg.

For measurements, the following protocol was utilized. Six animals wereused in each run. For any given measure (e.g., time point), one foot ofeach of the 6 animals was tested and then the process was repeated forthe opposite foot. Mean values for the response were then computed basedon the two scores.

Data from this experiment are given in the following table, and theyindicate that selected compounds show analgesia at doses from 0.62 to6.2 μmol/kg.

    ______________________________________                                        Table Showing                                                                   Analgesic Dose of Selected Compounds in Hotbox Model                                Compound of                                                                              analgesic                                                    Example dose                                                                  Number (μmol/kg)                                                         ______________________________________                                        54             >6.2                                                             71 0.62                                                                       72 0.62                                                                       75 6.2                                                                        79 0.62                                                                       80 0.62                                                                       81 0.62                                                                       92 >6.2                                                                       95 >6.2                                                                     ______________________________________                                    

Protocol for Determination of Anti-Inflammatory Effects of NicotinicAcetylcholine Receptor Ligands

Male Sprague-Dawley rats (Charles River, Portage, Mich.) weighingapproximately 200 g are fasted 16 hours with free access to water.Adrenalectomized Sprague Dawley rats (Charles River, Portage, Mich.)used in selected studies are also fasted but given free access tosaline. On the day of the experiment, rats are weighed, and the volumeof each hindpaw is measured by water displacement using a Buxcoplethysmograph. In these studies, all test agents are solubilized insterile 0.9% saline, and administered by i.p. injection. At the time ofchallenge, 100 μl of a 1% carrageenan solution (Sigma) in sterile 0.9%saline is injected subcutaneously into the right hindpaw according tothe method of Winter et al (Winter, C. A., et al., Proc. Soc. Exp. Biol.Med., 111:544, 1962). After 2 hours (unless otherwise noted), left andright hindpaw volumes are remeasured for determination of edema.

Following injection of carrageenan into the footpad of a rat an acuteinflammatory reaction occurs over the next 2-6 hours. The paw swellsdramatically as evidenced by direct plethysmographic measurement of pawvolumes. The increase in paw volume, through physical pressure ontendons and nerves, and local inflammation, sensitizes nociceptors (i.e.pain receptors) to cause hyperalgesia (i.e. an increased response to anoxious stimulus).

Compound of Example 4 reduces carrageenan-induced paw edema with an ED₃₀of 0.21 μmol/kg, i.p. Moreover, compound of Example 4 is as efficaciousas dexamethasone to reduce paw edema (panel A, FIG. 6). The effect ofcompound of Example 4 on paw edema is prevented by the nicotinicacetylcholine receptor antagonist, mecamylamine (panel B, FIG. 6). Thesedata demonstrate that compound of Example 4 is active in a model used toestablish anti-inflammatory effects, and that the effects are mediatedby nicotinic acetylcholine receptors. In addition, the compounds offormula I with the variables as defined above in the method of treatingpain should be active in a method of reducing or treating inflammation,as the above data suggest.

These data also suggest compounds of this invention would also haveanti-inflammatory actions, and that the added benefit of reduction ofinflammation of these nicotinic acetylcholine ligands may contribute tosuperior pain relief.

Protocol for Measurement of Cardiovascular Effects in Dogs

Male beagle dogs were anesthetized with pentobarbital (35 mg/kg, i.v.)followed by constant i.v. infusion of pentobarbital (5 mg/kg/h). Theanimals were ventilated with room air by means of a mechanicalrespiration pump. Blood pressure was measured using a dual tipmicromanometer catheter (Millar, Model SPC-770, 7F) inserted into theheart left ventricle via the carotid artery. Compounds were injectedinto the right femoral vein via catheter. Hemodynamic variables werecomputed using XYZ Real Time Spreadsheet software on a signal processingworkstation (Modular Instruments, Inc.). Sixty minutes were allowedfollowing surgery to achieve a steady-state baseline for the measuredvariables. Test compounds were administered by i.v. bolus (10 nmol/kg)and compared for their relative ability to elicit changes in bloodpressure and heart rate over a five minute data collection period.

    ______________________________________                                        Table Showing                                                                   Cardiovascular effects of Example 1 vs. Example 19                                               Compound  Compound                                          of Example of Example                                                        Assay 19 1                                                                  ______________________________________                                        Increase in Diastolic                                                                          67.3      23.2                                                 Blood Pressure ± 3.2 ± 4.6                                              (mm Hg),                                                                      Increase in Heart Rate 26.0 7.8                                               (beats/min), ± 7.8 ± 2.9                                              ______________________________________                                    

The compound of Example 1 (the (R)-enantiomer of5-(azetidinylmethoxy)-2-chloropyridine increased blood pressureapproximately only 1/3 of that seen with compound of Example 19 (the(S)-enantiomer of 5-(azetidinylmethoxy)-2-chloropyridine). In addition,the compound of Example 1 increased the heart rate in the dogs only 1/3of that seen for the compound of Example 19. These data suggest that thecompound of Example 1 causes less robust effects on cardiovascularparameters than does the compound of Example 19 and is therefore a safercompound. That is, the (R)-isomer is safer than the (S)-isomer.

Prodrug Conversion in Dogs

Prodrugs of the form (R=ArCO, Z=Y=H, X=F) have been shown to convertrapidly to the active drug (R=Z=Y=H, X=F) following oral administrationto dogs. Data are shown in the Table. In each case, peak plasma levelsof parent (R=H) were observed within 0.6-0.8 hr, and at levels (C_(max))consistent with an efficacious dose of the parent. The efficiency ofconversion (F) varies from 27-61%. None of these compounds was active ina functional in vitro assay for activity at nicotinic receptors (K177cell line), suggesting that in vivo activity results from conversion tothe R=H form.

    ______________________________________                                                   C.sub.max                                                                              T.sub.max                                                                             t1/2  AUC.sub.0-∞                                                                    F†                              R (ng/ml) (hr) (hr) (ng•hr/ml) (%)                                    ______________________________________                                        PhCO       6.31     0.6     1.8   18.89  27.3                                   4-NO.sub.2 C.sub.6 H.sub.4 CO 6.01 0.8 1.9 18.76 27.1                         4-MeOC.sub.6 H.sub.4 CO 7.43 0.8 2.0 26.09 37.7                               4-FC.sub.6 H.sub.4 CO 3.25 0.8 1.6 9.35 13.5                                  4-ClC.sub.6 H.sub.4 CO 4.54 0.8 2.5 18.61 26.9                                4-MeC.sub.6 H.sub.4 CO 7.05 0.8 2.4 29.85 43.1                                4-MeO2CC.sub.6 H.sub.4 CO 10.31 0.8 1.8 42.37 61.2                          ______________________________________                                         †bioavailability estimated from a 20 nmol/kg IV dose of (R = H) in     a separate group of dogs                                                 

Beagle dogs were fasted overnight prior to dosing but were permittedfree access to water. Each of the prodrugs was administered to a groupof three animals at a dose of 200 nmol/kg. The formulation wasadminstered by oral gavage. The prodrugs were prepared as 200 nmol/ml (1ml/kg) solutions in normal saline. Blood samples from a jugular vein ofeach dog prior to dosing and 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6and 8 hours after drug administration. Plasma, separated from the redcells by centrifugation, was subjected to precolumn derivatizationfollowed by HPLC with fluorescence detection for quantitation of activedrug concentrations.

EXAMPLES

The following examples show how the specific examples were made fromeasily prepared or commercially available starting materials. Theprevious discussion on the preparation of compounds within the scope ofthis invention is also relevant with respect to general preparation ofthe starting reactants utilized to prepare the analgesics or compoundsclaimed and recited herein. The Examples presented in Tabular form arereadily made according to the procedures described herein for theexamples actually made. These examples are non-limiting and it isunderstood that compounds within the scope as recited herein are withinthe invention as well as uses thereof.

In this section some terms are specified in abbreviated form. Theseterms are as identified below adjacent to the abbreviation:

Boc, t-butyloxycarbonyl; Cbz, benzyloxycarbonyl; DMF,N,N-dimethylformamide; MED, minimally effective dose; THF,tetrahydrofuran; TFA, trifluoroacetic acid; TLC, thin layerchromatography; Ts, tosyl or p-toluenesulfonyl; OTs is tosylate orp-toluenesulfonate.

In terms of nomenclature as presented below in the examples, thecompounds of this class have generally been designated as 3-pyridylethers with the 3-position of the pyridyl ring having the ether (O)functionality linking the methylene-azetidinyl moiety. However, when thepyridyl ring is di- or multi-substituted, the actual numbering on thepyridyl ring may change so that, for example, the compound of formula Iis specifically described in Example 4 wherein the chloro substituent isat the 2-position of the pyridyl ring and the ether linkage is at the 5position. One of ordinary skill in the art can readily identify thecompounds.

Example 1 5-((2R)-Azetidinylmethoxy)-2-chloropyridine

1a. 5-((2R)-Azetidinylmethoxy)-2-chloropyridine

A solution of (R)-1-t-butyloxycarbonyl-2-azetidinemethanol (36.5 g,0.195 mol) in 195 mL of dichloromethane was treated with triethylamine(35.6 ml, 0.255 mol) and then p-toluenesulfonyl chloride (48.5 g, 0.254mol). The resulting mixture was stirred at room temperature for 16hours. A 10% solution of sodium hydroxide was added rapidly and themixture stirred for one hour. After phase separation, the aqueous phasewas extracted with additional dichloromethane, combined with the organicphase, washed with NaHCO₃ solution and brine, then dried (MgSO₄),filtered, and concentrated in vacuo to give 63.1 g of(R)-1-t-butyloxycarbonyl-2-toluensulfonyloxymethylazetidine (94.8%).Next, a solution of 2-chloro-5-hydroxypyridine (from Step 1g below, 24g, 0.185 mol) in DMF (690 mL) was treated with ground KOH (17.95 g,0.295 mol) and stirred for 30 minutes at 80° C. To this mixture wasrapidly added(2R)-1-t-butyloxycarbonyl)-2-toluensulfonyloxymethylazetidine (63.1 g)dissolved in DMF (395 mL) and the mixture was stirred for 16 hours at80° C. The mixture was concentrated in vacuo to remove the DMF and theresultant residue was diluted with water and extracted with EtOAc (3×).The organic extracts were combined, dried (MgSO₄), filtered andconcentrated in vacuo to give 58.5 g of unpurified product. Thismaterial was chromatographed (silica gel, 25% EtOAc in hexane) to give43.2 g of5-(1-t-butyloxycarbonyl-(2R)-azetidinylmethyloxy)-2-chloropyridine as aclear oil (74%). A solution of5-(1-t-butyloxycarbonyl-(2R)-azetidinylmethoxy)-2-chloropyridine (30 g,0.1 mol) in 450 mL of dichloromethane at 0° C. was treated with 225 mLof trifluoroacetic acid dropwise over a 30 minute period. After twohours, the bulk of the solvent was removed in vacuo and the residue wasdiluted with ethyl acetate, washed with 1.0 M K₂ CO₃ and brine, dried(Na₂ SO₄) and concentrated in vacuo to give 19.1 g of a yellow oil.Flash silica gel chromatography (90:10 CHCl₃ :MeOH then 90:10:0.5 CHCl₃:MeOH:NH₄ OH) gave 16.5 g of the title compound (83% yield): MS (CI/NH₃)m/z: 199 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ 2.21-2.43 (m, 2H),3.42-3.50 (m, ¹ H), 3.69-3.78 (m, ¹ H), 3.98-4.07 (m, 2H), 4.25-4.34 (m,¹ H), 7.22 (d, J=1.7 Hz, 2H), 8.07 (dd, 1.7, 2.0 Hz, ¹ H).

1b. Benzyl (R)-azetidin-2-one4-carboxylate

To a flask under nitrogen containing dibenzyl (R)-aspartic acid (BACHEM,6.5 g, 20.6 mmol) was added 82 mL of diethyl ether. The whiteheterogeneous mixture was cooled to 0° C., then 2.6 mL (2.23 g, 20.6mmol) of chlorotrimethylsilane was added, followed by stirring for 15minutes. Then 2.9 mL (2.08 g, 20.6 mmol) of triethylamine was added viasyringe. The resultant white heterogeneous mixture was stirred for 1hour and then quickly filtered through a medium fritted glass funnelfilter under a stream of nitrogen. The cloudy white filtrate was placedunder nitrogen and treated with 10.3 mL of 2 M t-butylmagnesium chloridein diethylether dropwise over a 20 minute period. The resultant lightyellow homogeneous solution was allowed to slowly warm to roomtemperature overnight and then cooled to 0° C. To this was slowly added50 mL of 2 N HCl that had been saturated with NH₄ Cl. This biphasicmixture was transferred to a separatory funnel, the layers wereseparated, and then the aqueous phase was extracted with ethyl acetateand dichloromethane. The organic extracts were combined, washed withbrine, dried (Na₂ SO₄) and concentrated in vacuo to give 6.65 g of ayellow oil which solidified upon standing. The yellow solid wastriturated with ethyl acetate and filtered to give 1.7 g of benzyl(R)-azetidin-2-one-4-carboxylate as a white crystalline solid. Themother liquors were combined, concentrated, triturated with diethylether, and filtered to give an additional 350 mg of the title compound.Combined yield 49%. MS (CI/NH₃) m/z: 206 (M+H)⁺, 223 (M=NH₄)⁺ ; ¹ H NMR(CDCl₃, 300 MHz) δ 3.08 (ddd, J=2.2, 2.8, 15.1 Hz, ¹ H), 3.34 (ddd,J=1.5, 5.9, 15.1 Hz, ¹ H), 4.22 (dd, J=2.8, 5.9 Hz, ¹ H), 5.21 (s, 2H),6.17 (s (br), ¹ H), 7.37 (m, 5H).

Step 1c. (R)-1-(t -butyloxycarbonyl)-2-azetidinemethanol

A dry round bottom flask was charged with 410 mg (2 mmol) of (R)-benzylazetidin-2-one-4-carboxylate and 10 mL of dry tetrahydrofuran, thenswept with nitrogen and cooled to 0° C. To this clear homogeneoussolution was added 10 mL of 1 M LiAlH₄ in THF dropwise via syringe.After 76 hours, the reaction was cooled to 0° C. and 400 μL of distilledwater was added slowly (vigorous gas evolution). The mixture was stirredfor 15 minutes and then 400 μL of 15% NaOH was added and the mixture wasstirred an additional 15 minutes. Finally, 800 μL of distilled water wasadded, the white heterogeneous reaction was allowed to warm to roomtemperature, and then filtered through a 1/2 inch plug of Celite andconcentrated in vacuo to give 420 mg of a light yellow oil. A portion ofthis oil (310 mg) was treated with 4 mL CH₂ Cl₂ followed by 460 mgdi-tert-butyldicarbonate (2.1 mmol). This cloudy, light yellow mixturewas stirred at room temperature for 4.5 hours and then concentrated invacuo to yield 632 mg of a yellow oil. Flash chromatography (silica gelwith 2:1 to 1:1 hexane:ethyl acetate) produced 167 mg of the titlecompound (61% yield): [α]_(D) ²⁰ +22.3 (c 1.28, CHCl₃); MS (CI/NH₃) m/z:188 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ 1.45 (s, 9H), 1.94 (m, ¹ H), 2.15(m, ¹ H), 3.68-3.92 (m, 5H), 4.44 (m, ¹ H).

1d. (R)-1-t-butyloxycarbonyl-2-azetidinemethanol

An alternative to the procedures of Examples 1b-1c,(R)-1-t-butyloxycarbonyl-2-azetidinemethanol was prepared fromγ-butyrolactone according to the procedure of Rodebaugh, R. M. andCromwell, N. H., (J. Heterocyclic Chem., 1969, 435). In this literatureprocedure, γ-butyrolactone was treated with bromine and catalyticphosphorus tribromide, then subsequently with benzyl alcohol and gaseoushydrogen chloride to afford benzyl α,γ-dibromobutyrate in 62% yield.This dibromide in ethanol was treated with one equivalent ofbenzhydrylamine and potassium carbonate at reflux for about 16 hours toafford benzyl N-diphenylmethylazetidine-2-carboxylate in 52% yield.Hydrogenolysis in MeOH over Pd(OH)₂ afforded racemicazetidine-2-carboxylic acid in 62% yield. Following the procedure ofRodebaugh, R. M. and Cromwell, N. H., (J. Heterocyclic Chem., 1969,993), racemic azetidine-2-carboxylic acid was converted to the N-Cbzderivative by treatment with benzyl chloroformate in aqueous NaOH at0-5° C. Following isolation in quantitative yield, the Cbz derivative inmethanol was treated with one equivalent of L-tyrosine hydrazide toprecipitate the tyrosine hydrazide salt of (R)-azetidine-2-carboxylicacid in 77-87% yield. (R)-1-Cbz-azetidine-2-carboxylic acid wasliberated from the salt by normal extractive procedures. Hydrogenolysisof the free acid by treatment of a methanol solution with hydrogen gasat 4 atm in the presence of 10% Pd/C for 19 h afforded(R)-azetidine-2-carboxylic acid, which was isolated in 88% yield bytrituration with methanol. This product was treated with di-tert -butyldicarbonate and N-methylmorpholine in dioxane/H₂ O (1:1) to afford(R)-1-Boc-azetidine-2-carboxylic acid in quantitative yield. Treatmentof a THF solution of (R)-1-Boc-azetidine-2-carboxylic acid withborane-methyl sulfide complex for 16 h at ambient temperature affordedthe title compound in 92% yield.

1e. (R)-1-benzyloxycarbonyl-2-azetidinemethanol

The title compound was prepared from D-methionine following theprocedure of Sugano and Miyoshi, Bull. Chem. Soc. Japan 1973, 46, 669.D-methionine (29.84 g, 200 mmol) was dissolved in H₂ 0 (100 mL) and 1 NNaOH (200 mL, 200 mmol) was added to give a homogeneous solution. Withcooling as necessary to maintain a temperature of ˜20° C.,p-toluenesulfonyl chloride was added (53.4 g, 280 mmol). Additional 1 NNaOH was added in small portions over 2 hours as needed to maintain thepH ˜9 (total ca. 280 mL) and then the mixture was stirred at ambienttemperature overnight. The mixture was acidified to pH 3-4 with 4.5 NHCl, then stored at -20° C. A crop of white crystals (26.1 g, 43%) wascollected. An additional crop separated as an amber oil, which wascollected and dried under vacuum to afford 24.8 g (41%). NMR and MS (m/z321, (M+NH₄)⁺) of both crops were consistent with pureN-tosyl-D-methionine. The combined crops of N-tosyl-D-methionine (53.5g, 176 mmol) were dissolved in HOAc (53 mL) and 88% HCO₂ H (106 mL),then methyl iodide (20 mL) was added and the mixture was allowed tostand in the dark overnight. The volatile components were evaporatedunder reduced pressure, and the residue was triturated repeatedly withethyl ether to afford a semi-solid residue, which was dissolved in 1 NNaOH (180 mL). The solution was kept at 90° C. for 3 hours whilemaintaining pH 6-7 by addition of 3 N NaOH. The solution was acidifiedto pH 2-3 with 3 N HCl and a white precipitate was collected byfiltration and dried to afford 28 g ofα-(N-p-tosylamino)-γ-butyrolactone. Additional crops were obtainedfollowing storage of the mother liquors at -20° C. to afford anadditional 8.3 g of product (combined yield 81%), mp 132-134° C. MS: m/z273 (M+NH₄ ⁺), 291 M+(NH₄)₂)⁺. Following the procedure of Miyoshi, etal., (Chem. Lett., 1973, 5-6), a suspension of(R)-α-(N-p-tosylamino)-γ-butyrolactone (20 g) in EtOH (150 mL) was heldat 65° C. while HBr(g) was bubbled into the the mixure. After themixture became homogeneous, slow bubbling of HBr was continued at 65° C.to maintain maximal saturation throughout the reaction. The volatilecomponents were evaporated, then the residue was chromatographed (silicagel; 30% EtOAc/hexane) to afford 17.8 g (ca. 65%) of(R)-N-tosyl-γ-bromonorvaline ethyl ester as a slightly yellow oil. MS:(CI/NH₃) m/z 301 (M-HBr+NH₄)⁺ ; 381 (M+NH₄)⁺ ; M+(NH₄)₂)⁺. ToN-tosyl-γ-bromonorvaline ethyl ester (24.24 g, 66.5 mmol) in DMF (725mL) was added H₂ O (3.64 mL) followed by 60% NaH (8 g). The mixture wasstirred at 10-20° C. for 20 min, after which the mixture was acidifiedwith 1 N HCl, the solvents were evaporated, and CH₂ Cl₂ was subsequentlyadded and evaporated twice. Addition of 10% HCl precipitated theproduct, which was collected and recrystallized from EtOAc/petroleumether to afford 12.3 g (72%) of (R)-N-tosylazetidine-2-carboxylic acidas white floculent crystals: mp 144-145° C.; [α]_(D) +146 (c 0.61,CHCl₃); MS (CI/NH₃) m/z 273 (M+NH₄)⁺. Further manipulations were carriedout as described in Abreo, et al., J. Med. Chem. 1996, 39, 817-825.Analysis of enantiomeric purity was carried out by conversion to theα-methylbenzylamide, and evaluation by ¹ H-NMR, which indicated a ca.4:1 mixture of enantiomers. This mixture (1.48 g, 5.8 mmol) was slurriedin liquid NH₃ (25 mL) at -78° C. Sodium metal was added until a darkblue color persisted for 30 minutes and then solid ammonium chloride wasadded until the blue color disappeared. The cold bath was replaced witha water bath as the ammonia was allowed to evaporate. The remainingwhite solid was carefully dissolved in H₂ O (30 mL) and HOAc to adjustthe mixture to pH 7.0. Then 1,4-dioxane (30 mL) andN-(benzyloxycarbonyloxy)succinimide (2.1 g, 8.7 mmol) were added and themixture was stirred for 2 h. The biphasic mixture was partitionedbetween saturated K2CO₃ and Et₂ O and the phases were separated. Theaqueous phase was acidified with 12 N HCl and then extracted with CH₂Cl₂. The organic phase was dried (MgSO₄), concentrated, andchromatographed (silica gel; CHCl₃ /MeOH/HOAc, 95:5:0.5) to afford acolorless oil (955 mg, 70%): MS (CI/NH₃) m/z: 236 (M+H)⁺ ; ¹ H NMR(CDCl₃, 300 MHz) δ 2.47-2.60 (m, 2H) 3.98-4.07 (m, 2H), 4.78-4.87 (m, ¹H), 5.65 (s, 2H), 7.28-7.40 (m, 5H). The resultant 1-benzyloxycarbonylazetidine-2-carboxylic acid (932 mg, 3.96 mmol) was dissolved in MeOH(20 mL) and L-tyrosine hydrazide (773 mg, 3.96 mmol) was added. Theslurry was heated at reflux for 10 minutes, allowed to cool to ambienttemperature and then filtered. The filter cake was dissolved in 6 M HCland extracted with EtOAc (2×). The organic fractions were combined,dried (MgSO₄) and concentrated to give (R)-1-benzyloxycarbonylazetidine-2-carboxylic acid as a colorless oil (403 mg, 55%): [α]_(D) ²⁰+104.7 (c 4.0, CHCl₃). The (R)-1-benzyloxycarbonylazetidine-2-carboxylic acid (2.0 g, 8.6 mmol) in THF (35 mL) was cooledto 0° and 1.0 M BH₃.THF (12.9 mL, 12.9 mmol) was added dropwise. Themixture was allowed to warm to ambient temperature and stirred for 2.5hours. A solution of 2 N HCl was carefully added and the heterogenousmixture was allowed to stir for 1 hour. The slurry was extracted withCH₂ Cl₂ and the organic phase was dried (MgSO₄), concentrated, andchromatographed (silica gel; EtOAc/hexane, 1:1) to afford the titlecompound as a colorless oil (1.46 g, 77%): [α]_(D) ²⁰ 15.5 (c 1.2,CHCl₃). MS (CI/NH₃) m/z: 222 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ1.93-2.08 (m, ¹ H) 2.18-2.29 (m, ¹ H), 3.72-4.01 (m, 4H), 4.47-4.58 (m,¹ H), 5.12 (s, 2H), 7.30-7.41 (m, 5H).

1f. 5-acetoxy-2-chloropyridine

To a solution of 5-amino-2-chloropyridine (40.0 g, 0.311 mol, Aldrich)in 180 mL of 3:1 1,2-dimethoxyethane/CH₂ Cl₂ at -10° C. was slowly addedboron trifluoride diethyl etherate (76.5 mL, 0.662 mol). Then a solutionof tert-butyl nitrite (44.4 mL, 0.373 mol) in 40 mL of1,2-dimethoxyethane was slowly added over 15 min such that the reactiontemperature remained below -5° C. The mixture was stirred for 10 min at-10° C. then warmed to 0° C. and stirred for an additional 30 min.Pentane was added and the solid was collected by suction filtration(cold pentane wash) to afford 69.1 g of the tetrafluoroborate diazoniumsalt. This was dissolved in 350 mL of acetic anhydride, warmed to 75° C.(N₂ evolution) and stirred for 3 h. The volatiles were removed in vacuoand the dark residue was diluted with Et₂ O and washed with saturatedaqueous NaHCO₃. The aqueous phase was extracted with Et₂ O. The combinedethereal extracts were washed with brine, dried (MgSO₄), andconcentrated. Purification by chromatography (silica gel; hexane/EtOAc90:10 to 70:30) afforded the title compound as a white solid (29.4 g,55%): mp 45° C.; ¹ H NMR (CDCl₃, 300 MHz) δ: 2.35 (s, 3H) 7.35 (d, J=8.5Hz, ¹ H), 7.48 (dd, J=2.9, 8.5 Hz, ¹ H), 8.21 (d, J=2.9 Hz, ¹ H); MS(CI/NH₃) m/z: 172, 174 (M+H)⁺ ; 189, 191 (M+NH₄)⁺.

1g. 2-chloro-5-hydroxypyridine

5-Acetoxy-2-chloropyridine (11.1 g, 64.7 mmol) from example 1f wasdissolved in MeOH at ambient temperature and solid potassium carbonate(4.47 g, 32.4 mmol) was added. After stirring for 2 h, the volatileswere removed in vacuo and the residue was diluted with Et₂ O and H₂ O.The aqueous phase was adjusted to pH 7 by the addition of 1 N aqueousHCl. The layers were separated and the aqueous phase was extracted twicewith Et₂ O. The combined organic extracts were dried (MgSO₄) andconcentrated to provide the title compound as a white solid (8.03 g,96%): mp 155° C.; ¹ H NMR (CD₃ OD, 300 MHz) δ 7.20-7.28 (m, 2H), 7.88(m, ¹ H); MS (CI/NH₃) m/z: 130,132 (M+H)⁺ ; 147,149 (M+NH₄)⁺.

Example 2 5-((2R)-Azetidinylmethyloxy)-2-chloropyridinep-toluenesulfonate

A flask containing 5-((2R)-azetidinylmethyloxy)-2-chloropyridine fromExample 1 (750 mg, 3.78 nmmol) was charged with 15 mL absolute ethanolfollowed by p-toluenesulfonic acid monohydrate (718 mg, 3.78 mmol,Aldrich). This mixture was stirred at room temperature for 15 minutesand then concentrated in vacuo. The resulting off white crystallinesolid was triturated with EtOAc, filtered, and placed in a vacuum ovenovernight (˜16 hours, ca. 15 mm Hg) to give the title compound as awhite crystalline solid (1.38 g, 99%): mp 158-161° C.; [α]_(D) ²⁰ +5.40°(c 1.05, MeOH); ¹ H NMR (DMSO-d₆, 300 MHz δ 8.88 (s (br), 2H), 8.19 (d,J=2.9 Hz, ¹ H), 7.46-7.58 (m, 4H), 7.11 (d, J=7.0 Hz, 2H), 4.73 (m, ¹H), 4.42 (dd, J=7.0, 11.4 Hz, ¹ H), 4.33 (dd, J=3.3, 11.4 Hz, ¹ H),3.86-3.97 (m, 2H), 2.35-2.55 (m, 2H); MS (CI/NH₃) m/z: 199 (M+H)⁺ ; 216(M+NH₄)⁺.

Example 3 5-((2R)-Azetidinylmethyloxy)-2-chloropyridine benzoate

A flask containing 5-((2R)-azetidinylmethyloxy)-2-chloropyridine fromExample 1 (780 mg, 3.93 mmol) was charged with 16 mL of absolute ethanoland swept with nitrogen. To this solution was added benzoic acid (480mg, 3.93 mmol). After 1 hour, the mixture was concentrated in vacuo togive a thick yellow oil. This oil was treated with 10 mL diethyl etherwith stirring for ten minutes which gave a fine white crystallineprecipitate. The solid was filtered off and washed with diethylether andplaced in a vacuum oven overnight (˜20° C., ca. 15 mm Hg) to give thetitle compound (1.1 g, 88%): mp 102-104° C.; [α]_(D) ²⁰ +5.35 (c 1.03,MeOH); ¹ H NMR (CDCl₃, 300 MHz) δ 8.02 (d, J=2.7 Hz, ¹ H), 7.92 (m, 2H),7.33-7.50 (m 5H), 7.10 (m, 2H), 4.64 (m, 2H), 4.23 (m, 2), 3.91 (m, 2H),2.44-2.65 (m, 2H); MS (CI/NH₃) m/z: 199 (M+H)⁺ ; 216 (M+NH₄)⁺.

Example 4 5-((2R)-Azetidinylmethyloxy)-2-chloropyridine hydrochloride

5-((2R)-Azetidinylmethyloxy)-2-chloropyridine from Example 1 (478 mg,2.4 mmol) was slurried in Et₂ O (100 mL) and HCl saturated in Et₂ O wasadded slowly at ambient temperature until no further solid precipitated.The solvent was removed and the yellow solid was recrystallized fromMeOH/Et₂ O to afford the title compound as a fine white powder (365 mg,64%): mp 116-117° C.; MS (CI/NH₃) m/z: 199/201 (M+H)⁺ ; ¹ H NMR (D₂ O,300 MHz) δ 2.65-2.76 (m, 2H), 4.03-4.21 (m, 2H), 4.42 (d, J=4.1 Hz, 2H),4.92-5.00 (m, ¹ H), 7.47 (d, J=8.8 Hz, ¹ H), 7.56 (dd, J=3.0, 8.8 Hz, ¹H), 8.15 (d, J=3.0 Hz, ¹ H). Anal. Calcd for C₉ H₁₂ Cl₂ N₂ O: C, 45.98;H, 5.14; N, 11.91; Found: C, 46.03; H, 5.06; N, 11.76. [α]_(D) ²⁰ +8.6(c 0.52, MeOH).

Example 5 5-((2R)-Azetidinylmethyloxy)-2-chloropyridine dihydrochloride

To a flask containing 5-((2R)-azetidinylmethyloxy)-2-chloropyridine fromExample 1 (25.0 g, 0.126 mol) in dichloromethane at 0° C. was added anexcess of a saturated solution of HCl in diethylether. After additionwas complete, the white heterogeneous mixture was concentrated in vacuo.Recrystallization from methanol and diethyl ether provided the titlecompound (30.5 g, 89%) as a white, hygroscopic solid: mp 113-115.[α]_(D) ²⁰ +11.8 (c 0.84, MeOH); ¹ H NMR (D₂ O, 300 MHz) δ 2.65-2.76 (m,2H), 4.03-4.21 (m, 2H), 4.42 (d, J=4.1 Hz, 2H), 4.95 (m, ¹ H), 7.47 (d,J=8.8 Hz, ¹ H), 7.56 (dd, J=3.0, 8.8 Hz, ¹ H), 8.15 (d, J=3.0 Hz, ¹ H).Anal. Calcd for C₉ H₁₃ Cl₃ N₂ O: C, 37.78; H, 4.72; N, 9.79. Found: C,37.50; H, 4.70; N, 9.55.

Example 6 (R)-3-(2-Azetidinylmethyloxy)pyridine dihydrochloride

Diethyl azodicarboxylate (1.2 mL, 7.9 mmol) was added to a stirredsolution of triphenylphosphine (2.1 g, 7.9 mmol) in THF (60 mL) at 0° C.After 15 minutes, (R)-1-(benzyloxycarbonyl)-2-azetidinemethanol (1.46 g,6.6 mmol, Step 1e above) in THF (6.6 mL) was added to the reactionvessel followed by 3-hydroxypyridine (690 mg, 7.3 mmol, Aldrich). Afterstirring for 18 h at ambient temperature the solvent was removed and theresidue was dissolved in CH₂ Cl₂ and washed with saturated K₂ CO₃, dried(MgSO₄), concentrated and chromatographed (silica gel; EtOAc/hexane,1:2) to afford a mixture (2.8 g) of(R)-1-(benzyloxycarbonyl)-3-((2-azetidinylmethyl)oxy)pyridine andtriphenylphosphine oxide: MS (CI/NH₃) m/z: 299 (M+H)⁺. A sample (1.6 g)of this mixture was dissolved in EtOH (25 mL) and stirred in thepresence of 10% Pd/C (320 mg) under an atmosphere of H₂ (1 atm) for 4 h.The reaction was filtered, concentrated and chromatographed (silica gel;CHCl₃ /MeOH/NH₄ OH, 90:10 to 90:10:0.5) to afford the free base of thetitle compound as an amber oil (465 mg, overall yield 75%): [α]_(D) ²⁰+5.8 (c 1.6, CHCl₃); MS (CI/NH₃) m/z: 165 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300MHz) δ 2.22-2.46 (m, 2H), 3.45-3.51 (m, ¹ H), 3.73 (dd, J=7.7, 8.5 Hz, ¹H), 4.00-4.10 (m, 2H), 4.26-4.35 (m, ¹ H), 7.21-7.24 (m, 2H), 8.22 (dd,J=2.9, 3.0 Hz, ¹ H), 8.33 (dd, J=1.5, 2.2 Hz, ¹ H). The(R)-3-((2-azetidinylmethyl)oxy)pyridine (450 mg, 2.74 mmol) was slurriedin Et₂ O (20 mL) and MeOH (˜2 mL), then Et₂ O saturated with HCl gas wasadded at ambient temperature. The solvent was removed and the remainingsolid recrystallized from MeOH/Et₂ O to afford the title compound as adeliquescent white solid (206 mg, 31%): mp 138-140° C.; [α]_(D) ²⁰ +9.8(c 0.5, MeOH). MS (CI/NH₃) m/z: 165 (M+H)⁺ ; ¹ H NMR (D₂ O, 300 MHz) δ2.71 (dd, J=8.5, 17.3 Hz, 2H) 4.05-4.21 (m, 2H), 4.57 (d, J=4.4 Hz, 2H),4.96-5.03 (m, ¹ H), 7.99 (dd, J=5.7, 9.0 Hz, ¹ H), 8.21 (ddd, J=1.2,2.8, 9.0 Hz, ¹ H), 8.46 (d, J=5.7 Hz, ¹ H), 8.59 (d, J=2.8 Hz, ¹ H);Anal. Calcd for C₉ H₁₂ N₂ O.2 HCl.0.2 H₂ O: C, 44.90; H, 6.03; N, 11.64.Found: C, 44.90; H, 5.98; N, 11.54.

Example 7 (S)-3-(2-Azetidinylmethyloxy)pyridine dihydrochloride

7a. (S)-3-((2-Azetidinylmethyl)oxy)pyridine dihydrochloride

An ice-cooled solution of 1-butyloxycarbonyl-2-(S)-azetidinemethanol(2.8 g, 15.0 mmol, Step 7c below) in THF (40 mL) was stirred under anitrogen atmosphere. To this was added DEAD (3.54 mL, 22.46 mmol)followed by triphenylphosphine (4.78 g, 22.5 mmol) and the mixture wasstirred 10 minutes. 3-Hydroxypyridine (2.14 g, 22.5 mmol) was then addedto the reaction with additional tetrahydrofuran (40 mL). After 18 h,additional 3-hydroxypyridine (0.10 g, 1.05 mmol) was added and thereaction stirred 24 hours longer. When all starting azetidine alcoholwas consumed, the reaction mixture was concentrated in vacuo. The crudemixture was then acidified (pH<2) with a 10% solution of potassiumhydrogen sulfate (80 mL), and washed with ethyl acetate (3×75 mL). Theaqueous portion was then basified with a saturated solution of potassiumcarbonate (pH=10) and products extracted with ethyl acetate (4×75 mL).These extracts were dried (MgSO₄), filtered and concentrated in vacuo toa red-brown oil (1.84 g, 50% yield). Purification by flash silica gelchromatography Rf=0.19, (ethyl acetate:hexane=2:1) afforded the coupledproduct as a light yellow oil in 25% yield; MS (CI/NH₃) m/z 265 (M+H)⁺,282 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ: 8.36-8.35 (dd, J=3.7 Hz, J=0.7 Hz, ¹H), 8.24-8.22 (dd, J=4.0 Hz, J=1.5 Hz, ¹ H), 7.25-7.22 (m, 2H),4.56-4.48 (m, ¹ H), 4.36-4.31 (dd, J=10 Hz, J=4.9 Hz, ¹ H), 4.17-4.12(dd, J=10 Hz, J=2.9 Hz, ¹ H), 3.92-3.87 (dd, J=8.2 Hz, J=6.8 Hz, 2H),2.42-2.25 (m, 2H), 1.42 (s, 9H). To an ice-cooled solution of thecompound from above (286 mg, 1.08 mmol) in absolute ethanol (4 mL), wasadded a hydrogen chloride saturated ethanol solution (4 mL), undernitrogen. The reaction mixture was stirred 18 hours while graduallywarming to room temperature. The reaction mixture was then concentratedin vacuo, the product dissolved in absolute ethanol and triturated withdiethyl ether. Two recrystallizations from ethanol and diethyl etheryielded pure title compound as a white powder (174 mg, 87 mmol, 81%yield): mp 135-137° C.; [α]_(D) -5.0 (c 0.4, MeOH); MS (CI/NH₃) m/z 165(M+H)⁺, 182 (M+NH₄)⁺. ¹ NMR (D₂ O, 300 MHz) δ: 8.60-8.59 (d, J=2.9 Hz, ¹H), 8.48-8.46 (d, J=5.8 Hz, ¹ H), 8.25-8.21 (ddd, J=9.0 Hz, J=2.6 Hz,J=1.1 Hz, ¹ H), 5.05-4.97 (m, ¹ H), 4.59-4.57 (d, J=4.0 Hz, 2H),4.22-4.05 (m, 2H), 2.77-2.67 (dd, J=16.9 Hz, J=8.45 Hz, 2H). Anal.calcd. for C₉ H₁₂ N₂ O.2.7 HCl.0.2 H₂ O: C, 40.60; H, 5.71; N, 10.52.Found: C, 40.75; H, 5.76: N, 10.51.

7b. 1-butyloxycarbonyl-2-(S)-azetidine carboxylic acid

To an ice-cooled solution of 2-(S)-azetidinecarboxylic acid (10.2 g, 100mmol, Aldrich) in 300 mL of 1:1 water/1,4-dioxane was addeddi-tert-butyl dicarbonate (28.5 g, 131 mmol), followed by4-methylmorpholine (11.7 g, 115 mmol). The reaction mixture was warmedto ambient temperature and stirred for 18 hours. The reaction mixturewas then poured into a ice cooled saturated solution of sodiumbicarbonate (250 mL) and washed with ethyl acetate. The aqueous phasewas then acidified with potassium hydrogen sulfate (pH=1) and theproduct extracted with ethyl acetate. These organic extracts were dried(Na₂ SO₄), filtered and concentrated in vacuo to afford the titlecompound as a white semisolid: MS (CI/NH₃) m/z 202 (M+H)⁺, 219 (M+NH₄)⁺; ¹ H NMR (CDCl₃, 300 MHz) δ 10.0 (br s, ¹ H), 4.81-4.76 (t, J=15 Hz, ¹H), 3.99-3.83 (m, 2H), 2.62-2.38 (m, 2H), 1.48 (s, 9H).

7c. 1-t-butyloxycarbonyl-(2S)-azetidinemethanol

To an ice-cooled solution of the compound from Step 7b (9.39 g, 46.7mmol) in THF (100 mL) was added borane.THF complex (1 M, 210 mL, 4.50eq.) under nitrogen. The reaction was gradually warmed to roomtemperature and stirred for 48 hours. A 10% aqueous potassium hydrogensulfate solution (60 mL) was added gradually, and the volatilecomponents were then evaporated in vacuo. The remaining slurry wasextracted with EtOAc. The organic extracts were washed with a saturatedsolution of aqueous sodium hydrogen carbonate, dried (MgSO₄), filteredand concentrated in vacuo, providing the title compound as a colorlessoil (8.4 g, 96%): MS (CI/NH₃) m/z 188 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz)δ 4.49-4.40 (ddd, J=9.0 Hz, J=9.0 Hz, J=3.0 Hz, ¹ H), 3.95-3.68 (m, 4H),2.23-2.12 (m, ¹ H), 1.99-1.87 (m, ¹ H), 1.46 (s, 9H).

Example 8 5-(2R)-Azetidinylmethyloxy)-2-fluoropyridine dibenzoate

8a. 5-(2R)-Azetidinylmethyloxy)-2-fluoropyridine dibenzoate

To a solution of triphenylphosphine (0.80 g, 3.0 mmol) in THF (20 mL)was added diethyl azodicarboxylate (4.7 mL, 3.0 mmol) at 0° C., and themixture was stirred for 0.5 h.1-t-butyloxycarbonyl-2-(R)-azetidinemethanol (0.51 g, 2.7 mmol, fromExample 1c above) and 2-fluoro-5-hydroxypyridine (0.32 g, 2.8 mmol, Step8e below) were then added. The mixture was allowed to warm slowly toroom temperature and stirred overnight. The solvent was removed and theresidue was chromatographed (silica gel; hexane/EtOAc, 9:1 to 7:3) toprovide 0.80 g of the coupled product: MS (CI/NH₃) m/z 283 (M+H)⁺, 300(M+NH₄)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ 1.42 (m, 9H), 3.33 (m, ¹ H),3.89(t, J=7.31 Hz,1H), 4.11 (m ¹ H), 4.31 (m, ¹ H), 4.51 (m, ¹ H), 6.85 (m,¹ H), 7.38 (m, ¹ H), 7.87 (m, ¹ H). The6-fluoro-3-(1-t-butyloxycarbonyl-2-(R)-azetidinylmethoxy)pyridine (760mg, 2.70 mmol) was combined with TFA (2 mL) in methylene chloride (2 mL)at 0° C., and the solution was stirred for 30 minutes. The volatilecomponents were then removed under vacuum. The residue was basified withsaturated aqueous NaHCO₃ and extracted with methylene chloride. Theorganic extract was dried over MgSO₄ and concentrated. The residue waschromatographed (silica gel: methylene chloride:methanol:NH₄ OH10:1:0.1) to afford of the free base of the title compound (240 mg,49%). The base was converted to the dibenzoic acid salt by treatmentwith benzoic acid in ether to give the title compound (235 mg, 42%): mp76-80° C.; [α]_(D) 2.9 (c 1, MeOH); MS (CI/NH₃) m/z 183 (M+H)⁺ ; ¹ H NMR(D₂ O, 300 MHz) δ 2.23 (m, ¹ H), 2.34 (m, ¹ H), 3.49(m, ¹ H), 3.66 (m, ¹H), 4.14 (m, ¹ H), 4.35 (m, ¹ H), 7.12 (dd, J=2.44, 8.81 Hz, ¹ H), 7.45(m, 4H), 7.56 (m, 2H), 7.63 (m, ¹ H), 7.93 (m, 3H); Anal. Calcd. for C₉H₁₁ N₂ OF.2 C₆ H₅ COOH: C, 64.78 H, 5.44; N, 6.57. Found: C, 64.65 H,5.48; N, 6.45.

8b. 2-fluoro-5-nitropyridine

2-Chloro-5-nitropyridine (100 g, 0.656 mol, Aldrich), potassium fluoride(84.1 g, 1.45 mol, Aldrich), tetraphenylphosphonium bromide (95.3 g,0.227 mol, Aldrich), and acetonitrile (1.5 L) were combined and heatedat reflux until consumption of the 2-chloro-5-nitropyridine wascomplete. The volume of the mixture was reduced to 750 mL, diluted with2 L of ether, filtered and concentrated. The resultant residue wastriturated with hot hexane, and the combined hexane extracts wereconcentrated to give of the title compound (48 g, 54%): ¹ H NMR (CDCl₃,300 MHz) δ 7.15 (dd, J=3, 6 Hz, ¹ H), 8.64 (m, ¹ H), 9.15 (d, J=1.6 Hz,¹ H).

8c. 3-Amino-6-fluoropyridine

2-Fluoro-5-nitropyridine (52.4 g, 368 mmol, from Step 8b above) wascombined with 5% Pd/C (100 mg, Aldrich) in EtOH (100 mL) and the mixturewas stirred under a H₂ atmosphere for 4 days. The mixture was filteredand concentrated. The crude product was chromatographed (silica gel;hexane/EtOAc, 9:1 to 1:1) to give 30.9 g (75%) of the title compound: ¹H NMR (DMSO-d₆, 300 MHz) δ 6.74 (dd, J=3, 6 HzH, ¹ H), 7.11 (m, ¹ H),7.26 (t, J=1 Hz, ¹ H), MS (CI/NH₃) m/z 113 (M+H)⁺, 130 (M+NH₄)⁺.

8d. 3-acetoxy-6-fluoropyridine

A solution of 3-amino-6-fluoropyridine (5.0 g, 45 mmol, from Step 8cabove) dissolved in DME (30 mL) was added to a cooled solution (-15° C.)of boron trifluoride etherate (12.2 mL, 99 mmol). tert-Butyl nitrite(6.3 mL, 54 mmol) was then added at a rate which maintained thetemperature below 0° C. After 10 minutes at -10° C. the reaction waswarmed to 5° C. and stirred for 30 min. Pentane (150 mL) was then addedto the reaction mixture, and the resultant solid was collected bysuction filtration, washed with cold ether, air dried, and dissolved inacetic anhydride (75 mL). The solution was heated to 105° C. untilnitrogen evolution ceased. The solvent was removed in vacuo, and theresidue was suspended in saturated aqueous Na₂ CO₃ (200 mL) andextracted with ethyl ether (2×150 mL). The combined organic extractswere dried (MgSO₄) and concentrated. Purification by chromatography(silica gel; hexane/EtOAc, 9:1 to 7:3) afforded the title compound (2.25g, 33%): ¹ H NMR (CDCl₃ 300 MHz) δ 2.32 (s, 3H), 6.96 (d, J=3, 9 Hz, ¹H), 7.59 (m, ¹ H), 8.03 (dd, J=0.5, 1 Hz, ¹ H); MS (CI/NH₃) m/z 156(M+H)⁺, 171 (M+NH₄)⁺.

8e. 2-Fluoro-5-hydroxypyridine

5-acetoxy-2-fluoropyridine (2.26 g, 14.6 mmol, from step 8d above) wasdissolved in 20% aqueous NaOH (15 mL). After stirring at ambienttemperature for 1 hour the solution was neutralized by addition ofconcentrated HCl. The aqueous mixture was extracted with ethyl acetate.The combined organic extracts were dried (MgSO₄), and the solvent wasevaporated. Purification by chromatography (silica gel; CHCl₃ /MeOH,98:2) afforded 1.31 g (79%) of the title compound: MS m/z: 114 (M+H)⁺,131 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ 6.84 (dd, J=1.85, 5.14 Hz, ¹H), 7.43 (m, 1 H), 7.81 (t, J=2.84 Hz, ¹ H).

Example 9 5-(2S)-Azetidinylmethyloxy)-2-fluoropyridine dibenzoate

Following the procedures of Example 8, replacing the1-t-butyloxycarbonyl-2-(R)-azetidinemethanol thereof with1-t-butyloxycarbonyl-2-(S)-azetidinemethanol, the title compound wasprepared: mp 76-80° C.; MS (CI/NH₃) m/z 183 (M+H)⁺ ; ¹ H NMR (D₂ O, 300MHz) δ 2.65 (m, 2H), 4.11 (m, 2H), 4.38 (d, J=4.39 Hz 2H), 4.92 (m, ¹H), 7.09 (dd, J=2.83, 9.28 Hz, ¹ H), 7.50(m, 4H), 7.56 (m, 2H), 7.63 (m,¹ H), 7.92 (m, 4H). Anal. Calcd for C₉ H₁₁ N₂ OF.2 C₆ H₅ CO₂ H: C, 64.78H, 5.44; N, 6.57. Found: C, 64.55 H, 5.46 N, 6.59.

Example 10 5-((2S)-Azetidinylmethyloxy)-3-fluoropyridine dihydrochloride

10a. 5-((2S)-Azetidinylmethyloxy)-3-fluoropyridine dihydrochloride

A solution of 3-fluoro-5-hydroxypyridine (500 mg, 4.43 mmol, as preparedin step 10f below) in dimethylformamide (20 mL) was treated with groundKOH (400 mg, 7.10 mmol) and stirred for 30 minutes at 80° C. To thismixture was rapidly added the1-(t-butyloxycarbonyl)-(2S)-p-toluene-sulfonyloxymethylazetidine (1.05g, 4.39 mmol, as prepared in Step 10b below) dissolved indimethylformamide (5 mL) and the reaction mixture was subsequentlystirred for 16 h at 80° C. The mixture was concentrated to remove thedimethylformamide and the resultant residue diluted with water andextracted with EtOAc (3×). The organic extracts were combined, dried(MgSO₄), filtered and concentrated in vacuo. This material was purifiedby flash chromatography (silica gel; hexane/EtOAc, 10:1) to give5-fluoro-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (692mg, 56%): ¹ H NMR (CDCl₃, 300 MHz) δ 1.40 (s, 9H), 2.30 (m, 2H), 3.92(m, 2H), 4.16 (m, ¹ H), 4.40 (m, ¹ H), 4.54 (m, ¹ H), 7.05 (m, ¹ H),8.20 (m, 2H); MS (CI/NH₃) m/z: 283 (M+H)⁺. To5-fluoro-3-(1-Boc-(2S)-azetidinylmethoxy)pyridine from above (320 mg,1.14 nmuol) was added HCl/Et₂ O in methylene chloride at 0° C., and thesolution was stirred for 2 h. The solvent was removed and the residuewas recrystallized from EtOH/Et₂ O to afford the tide compound (250 mg):mp 165-167° C.; [α]_(D) ²⁵ 27.8 (c 0.56, MeOH); ¹ H NMR (D₂ O, 300 MHz)δ 2.70 (m, 2H), 4.10 (m, 2H), 4.50 (d, J=4.5 Hz, 2H), 5.01 (m, ¹ H),7.80 (tt, J=3 Hz, ¹ H), 8.42 (dd, J=3, 6 Hz, 2H); MS (CI/NH₃) m/z 183(M+H)⁺, 200 (M+NH₄)⁺.

10b. (S)-1-t-butyloxycarbonyl-2-toluensulfonyloxymethylazetidine

A solution of (2S)-1-t-butyloxycarbonyl-2-azetidinemethanol (22.6 g,0.121 mol) in 40 mL of pyridine was treated with p-toluenesulfonylchloride (27.6 g, 0.145 mol). The resulting mixture was stirred at roomtemperature for 16 hours, diluted with CH₂ Cl₂ and washed sequentiallywith 1 N aqueous HCl, H₂ O, saturated aqueous K₂ CO₃, and brine. Theorganic phase was dried (Na₂ SO₄) and concentrated. Purification bychromatography (silica gel; Hexane/EtOAc, 80:20) afforded 32.8 g of awhite solid which was recrystallized from CH₂ Cl₂ /hexane to afford thetitle compound as thin white needles: mp 59-60° C.; ¹ H NMR (CDCl₃, 300MHz) δ 1.37 (s, 9H), 2.15-3.28 (m, 2H), 2.44 (s, 3H), 3.74-3.81 (m, 2H),4.13 (dd, J=3.1, 10.2 Hz, ¹ H), 4.23-4.34 (m, 2H), 7.35 (d, J=8.1 Hz,2H), 7.80 (d, J=8.2 Hz, 2H); MS (CI/NH₃) m/z: 242 (M+H)⁺.

10c. 3-benzyloxy-5-bromopyridine

NaH (60% in mineral oil) (40.9 g 1.0225 mol) in 800 mL of DMF was cooledto 0° C., and benzyl alcohol (105 mL 1.014 mol) was added slowly. Thereaction mixture was stirred for 1 hour at 20° C., then3,5-dibromopyridine (200.4 g, 846 mmol) was added and the mixture wasstirred for 16 hours. The mixture was quenched with saturated NH₄ Cl(500 mL), diluted with water and extracted with Et₂ O. The combined Et₂O extracts were washed with 50% brine and dried (MgSO₄). The solvent wasevaporated in vacuo and the crude product was recrystallized from Et₂ Oto afford the title product (161 g,72%): mp 63-68° C.; ¹ H NMR (CDCl₃,300 MHz) δ 8.37-8.27 (m, 2H), 7.5-7.35 (m, 6H), 5.1 (s, ¹ H), MS(CI/NH₃) m/z 264, 266 (M+H)⁺.

10d. 3-amino-5-benzyloxypyridine

The product of Example 10c above (41.3 g 156 mmol), copper(I) bromide(22.43 g 156 mmol), MeOH (275 mL), and liquid NH₃ (50 mL) were combinedin a stainless steel reactor and heated to 130° C. for 24 hours. Themixture was allowed to cool to ambient temperature, then concentrated.The residue was suspended in 300 mL of saturated aqueous Na₂ CO₃ andextracted with CH₂ Cl₂. The combined CH₂ Cl₂ solutions were washed withbrine, dried (MgSO₄), and concentrated. The crude product waschromatographed (silica gel; hexane/EtOAc, 9:1 to 7:3) to afford thetitle compound (15.6 g, 50%): ¹ H NMR (CDCl₃, 300 MHz) δ: 8.21-8.29 (m,2H), 7.44-1.26 (m, 6H), 5.10 (s, 2H); MS (CI/NH₃) m/z 201 (M+H)⁺.

10e. 3-fluoro-5-benzyloxypyridine

To boron trifluoride etherate (9.3 mL, 75 nunol) cooled to -15° C. underN₂ was added the product of Example 10d (10 g, 50 mmol) dissolved in DME(100 mL). tert-Butyl nitrite (7.8 mL, 65 mmol) was added at a rate whichkept the temperature below -5° C. After 10 minutes at -10° C. thereaction was warmed to 5° C. and stirred for 30 minutes. Pentane (200mL) was then added to the reaction mixture, and the solid was collectedby suction filtration, washed with cold ether, and then dissolved inacetic anhydride (150 mL). The resulting solution was heated to 70° C.until N₂ evolution stopped. The solvent was removed in vacuo, and theresidue was suspended in saturated aqueous Na₂ CO₃ and extracted withdiethyl ether. The ether solution was dried (Na₂ SO₄) and concentrated.The crude product was chromatographed (silica gel; hexane/EtOAc, 6:1) toyield 2.0 g of the title compound: ¹ H NMR (CDCl₃, 300 MHz) δ: 5.17 (s,2H), 7.04 (tt, J=3 Hz, 1H), 7.41(m, 5H), 8.15 (d, J=3 Hz, ¹ H), 8.25 (d,J=3 Hz, ¹ H); MS (CI/NH₃) m/z 204 (M+H)⁺, 221 (M+NH₄)⁺.

10f 3-fluoro-5-hydroxypyridine

The product of Example 10e (2.0 g, 9.85 mmol) in MeOH (50 mL) wasstirred under an atmosphere of H₂ in the presence of 10% Pd/C (50 mg)for 4 hours. The mixture was filtered and concentrated to afford 1.1 g(93%) of the title compound as white solid: ¹ H NMR (300 MHz) δ: 7.78(tt, J=3 Hz, ¹ H), 8.38 (d, J=3 Hz, ¹ H), 8.56 (d, J=3 Hz, ¹ H), 7.41(m,10.72 (b, ¹ H); MS (CI/NH₃) m/z 114 (M+H)⁺, 131 (M+NH₄)⁺.

Example 11 5-((2R)-Azetidinylmethyloxy)-3-fluoropyridine dibenzoate

The procedure of Example 10a was followed, replacing the1-t-butyloxycarbonyl-2(S)-p-toluensulfonyloxymethylazetidine with thecorresponding (R) isomer (Example 1c) to give the free amine compound(65%): ¹ H NMR (CDCl₃, 300 MHz) δ: 1.42 (s, 9H), 2.30 (m, 2H), 3.92 (m,2H), 4.16 (dd, J=3 Hz, ¹ H), 4.38 (m, ¹ H), 4.58 (m, ¹ H), 7.05 (tt, J=3Hz, ¹ H), 8.20 (dd, J=3 Hz, 2H); MS (CI/NH₃) m/z 283 (M+H)⁺. To5-(N-Boc-(2R)-azetidinylmethyloxy)-3-fluoropyridine from above (692 mg,2.45 mmol) was added HCl/Et₂ O in methylene chloride at 0° C., and thesolution was stirred for 2 hours. The solvent was removed and theresidue was recrystallized from EtOH/Et₂ O to afford the title compound(365 mg): mp 163-165° C.; [α]_(D) ²⁵ -30.0 (c 0.51, MeOH); ¹ H NMR (D₂O, 300 MHz) δ 2.72 (m, 2H), 4.15 (m, 2H), 4.52 (d, J=4.5 Hz, 2H), 4.98(m, ¹ H), 7.40 (d, J=12 Hz, ¹ H), 8.42 (b, 2H); MS (CI/NH₃) m/z 183(M+H)⁺, 200 (M+NH₄)⁺. Anal. Calcd for C₉ H₁₂ FClN₂ O.0.3HCl: C, 47.08;H, 5.40; N, 12.20. Found: C, 47.25; H, 4.90; N, 12.04.

Example 12 5-((2S)-Azetidinylmethyloxy)-3-bromopyridine dihydrochloride

12a. 5-((2S)-Azetidinylmethyloxy)-3-bromopyridine dibenzoate

Triphenylphosphine (4.01 g, 15.3 mmol) and DEAD (2.43 mL, 15.3 mnol)were dissolved in 30 mL of THF at 0° C., and the mixture was stirred for10 minutes. Samples of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol(2.86 g, 15.3 mmol, Step 7c above) and 3-bromo-5-hydroxypyridine.(1.51g, 10.2 mmol, Step 10c above) were added, and the mixture was stirredfor 40 hours at room temperature. The volatile components were removedunder vacuum, and the residue was triturated with hexane. The separatedhexane fraction was concentrated, and the residue was chromatographed(silica gel; hexane/ether, 10:1 to 10:2) to afford5-bromo-3-((1-t-butyloxycarbonyl-(2S)-azetidinyl)methoxy)pyridine as acolorless oil (1.669 g): ¹ H NMR (CDCl₃, 300 MHz) δ 1.42 (s, 9H), 2.31(m, 2H), 3.89 (m, 2H), 4.12 (m, ¹ H), 4.322 (m, ¹ H), 4.52 (m, ¹ H),7.43 (m, ¹ H), 8.29 (m, 2H); MS (CI/NH₃) m/z 344 (M+H)⁺. The5-bromo-3-(2-(1-BOC-2-(S)-azetidinyl)methoxy)pyridine was treated withwith 4 M HCl in dioxane to give the free base of the title compound.This was converted to the dihydrochloride salt and recrystallized frommethanol/ether to provide the title compound: mp 163-165° C.; [α]²⁵ _(D)-5.1 (c 0.57, methanol); ¹ H NMR (D₂ O, 300 MHz) δ 8.36 (d, J=1.8 Hz, ¹H), 8.32 (d, J=2.6 Hz, ¹ H), 7.84 (dd, J=1.8, 2.6 Hz, ¹ H), 4.98-4.90(m, ¹ H), 4.43 (d, J=4.0 Hz, 2H), 4.20-4.02 (m, 2H), 2.67 (q, J=8.5 Hz,2H); MS (CI/NH₃) m/z 243/246 (M+H)⁺, 260/262 (M+NH₄)⁺. Anal. calcd forC₉ H₁₃ N₂ OBrCl₂ : C, 34.21; H, 4.15; N, 8.86. Found: C, 34.18; H, 4.17;N, 8.89.

12b. 3-Bromo-5-hydroxypyridine

3-Benzyloxy-5-bromopyridine from Example 10c was heated at reflux with48% HBr/HOAc (60 mL) for 16 hours. The reaction was quenched with excessNaHCO₃, the basic mixture was extracted with ethyl acetate, and theextract was dried over Na₂ SO₄. The solvent was removed, and the residuewas chromatographed (silica gel; MeOH/CCl₄, 1/10) to afford the titlecompound: ¹ H NMR (CDCl₃, 300 MHz) δ 8.27 (d, J=1.8 Hz, ¹ H), 8.23 (d,J=2.6 Hz, ¹ H), 7.44 (dd, J=1.8, 2.6 Hz, ¹ H); MS (CI/NH₃) m/z 174, 176(M+H)⁺, 191, 193 (M+NH₄)⁺.

Example 13 5-Methyl-3-((2S)-Azetidinylmethyloxy)pyridine dibenzoate

To a solution of5-bromo-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (400 mg,1.20 mmol, Step 12a above) in THF (10 mL) at 0° C. was added a catalyticamount of [1,3-bis(diphenylphosphino)-propane]nickel(II) chloride (3.8mg) followed by MeMgBr (0.8 mL of a 3.0 M solution in THF, Aldrich). Themixture was refluxed for 3 hours, cooled to ambient temperature, andquenched with saturated aqueous ammonium chloride. The volatilecomponents were evaporated and the residue was diluted with CH₂ Cl₂ andsaturated aqueous ammonium chloride. The organic extract was dried overMgSO₄ and concentrated. The residue was chromatographed (silica gel; CH₂Cl₂ /MeOH, 10:0.2 to 10:0.5) to afford the5-methyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethyloxy)pyridine as anoil (177 mg, 53%): ¹ H NMR (CDCl₃, 300 MHz) δ 1.42 (s, 9H), 2.20-2.40(m, 2H), 3.90 (t, J=8.33 Hz, 2H), 4.14 (m, ¹ H), 4.31 (m, ¹ H), 4.51 (m,¹ H), 7.04 (s, ¹ H), 8.06 (s, ¹ H), 8.18 (d, J=3.33 Hz, ¹ H); MS(CI/NH₃) m/z 279 (M+H)⁺. To a solution of the above product (170 mg, 0.6mmol) in CH₂ Cl₂ (2 mL) at 0° C. was added TFA (1.0 mL). After stirringfor 30 minutes the solution was basified with 15% aqueous NaOH andextracted with CH₂ Cl₂. The combined organic extracts were dried overMgSO₄ and concentrated. The crude product was chromatographed (silicagel; CH₂ Cl₂ /MeOH, 10:1) to afford5-methyl-3-(azetidinyl-(2S)-methoxyl)pyridine as an oil (93 mg, 64%): ¹H NMR (CDCl₃, 300 MHz) δ 2.28 (m, ¹ H), 2.36 (s, 3H), 2.39 (m, ¹ H),3.43 (m, ¹ H), 3.65 (q, J=3.33 Hz, ¹ H), 3.98-4.02 (m, 2H), 4.22 (m, ¹H), 7.12(m, ¹ H), 8.04 (s, ¹ H), 8.14 (d, J=3.33 Hz, ¹ H); MS (CI/NH₃)m/z: 179 (M+H)⁺. The above product was slurried in Et₂ O and HCl in Et₂O was added dropwise. The solvent was removed and the resultant solidwas recrystallized from MeOH/Et₂ O to afford the title compound as alight yellow, very hygroscopic solid: ¹ H NMR (D₂ O, 300 MHz) δ 2.36 (s,3H), 2.67 (q, J=8.33 Hz, 2H), 4.04-4.21 (m, 2H), 4.40 (d, J=3.40 Hz,2H), 4.90 (m, ¹ H), 7.40 (s, ¹ H), 8.04 (s, ¹ H), 8.14 (s, ¹ H). MS(CI/NH₃) m/z: 179 (M+H+)⁺. Anal. Calcd. for C₁₀ H₁₄ N₂.1.5 HCl: C,51.57; H, 6.71; N, 12.03. Found: C, 51.53; H, 6.86; N, 12.03.

Example 14 5-Methyl-3-((2R)-azetidinylmethyloxy)pyridine hydrochloride

Following the procedures of Example 12a, replacing the1-t-butyloxycarbonyl-(2S)-azetidinemethanol thereof with1-t-butyloxycarbonyl(2R)-azetidinemethanol (from Example 1d),5-bromo-3-(1-t-butyloxycarbonyl-(2R)-azetidinylmethoxy)pyridine wasprepared. Following the procedures of Example 13, replacing5-bromo-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine thereofwith the enantiomeric5-bromo-3-(1-t-butyloxycarbonyl-(2R)-azetidinylmethoxy)pyridine, thetitle compound was prepared as a white solid: [α]_(D) -5.38 (c 0.93,MeOH); ¹ H NMR (D₂ O) δ 2.40 (s, 3H), 2.70 (q, 2H, J=9.30 Hz), 4.04-4.20(m, 2H), 4.42 (d, 2H, J=5.0 Hz), 4.95-5.00 (m, ¹ H), 7.45 (s, ¹ H), 8.08(s, ¹ H), 8.15 (s, ¹ H); MS (CI/NH₃): m/z 179 (M+H⁺), 196 (M+NH₄ ⁺).Anal. Calcd for C₁₀ H₁₄ N₂ O.1.5 HCl: C, 51.57; H, 6.71; N, 12.03.Found: C, 51.53; H, 6.86; N, 12.03.

Example 15 5-((2S)-azetidinylmethoxy)-2,3-dichloropyridine hydrochloride

15a. 5-((2S)-azetidinylmethoxy)-2,3-dichloropyridine hydrochloride

A solution of triphenylphosphine (2.6 g, 9.94 mmol) and diethylazodicarboxylate (1.6 mL, 9.94 mmol) in THF (16 mL) was stirred at 0° C.for 15 minutes. 1-t-Butyloxycarbonyl-2-(S)-azetidinemethanol (1.55 g,8.28 mmol, from step 7c above) and 5,6-dichloro-3-pyridinol (1.5 g, 9.1mmol) were then added. The reaction mixture was allowed to warm slowlyto room temperature and stir overnight. The solvent was removed, and theresidue was redissolved in methylene chloride. The solution was washedwith saturated aqueous K₂ CO₃ and brine, dried over MgSO₄ andconcentrated. The residue was chromatographed (silica gel; ethylacetate:hexane, 1:5) to afford the5,6-dichloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine(1.08 g): MS (CI/NH₃) m/z 333 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ 1.42(s, 9H), 2.22-2.42 (m, 2H), 3.85-3.92 (m, 2H), 4.12 (dd, J=2.7, 10.1 Hz,¹ H), 4.30-4.40 (m, ¹ H), 4.48-4.56 (m, ¹ H), 7.41 (d, J=2.8 Hz, ¹ H),7.97 (d, J=2.8 Hz, ¹ H). To a solution of5,6-dichloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)-pyridine(1.06 g, 3.11 mmol) in CH₂ Cl₂ (10 mL) at 0° C. was added TFA (10 mL).The solution was allowed to warm to room temperature while stirring for45 minutes. The volatile components were then removed under vacuum. Theresidue was treated with saturated K₂ CO₃ solution, then extracted withmethylene chloride. The organic extract was dried over MgSO₄ andconcentrated. The residue was chromatographed (silica gel; MeOH/CHCl₃/NH₄ OH, 1:10:0 to 1:10:0.05) to afford the free base of the titlecompound (475 mg, 64% yield): mp 59-60° C.; MS (CI/NH₃) m/z 233 (M+H)⁺ ;¹ H NMR (CDCl₃, 300 MHz) δ 2.21-2.44 (m, 2H), 3.45 (m, ¹ H), 3.73 (dd,J=8.4, 15.8 Hz, ¹ H), 3.98-4.08 (m, 2H), 4.28 (m, ¹ H), 7.37 (d, J=2.8Hz, ¹ H), 8.01 (d, J=2.8 Hz, ¹ H). The base (336 mg) was slurried inether and converted to the hydrochloride salt by treatment withsaturated HCl in ether. Recrystallization from methanol/ether gave thetitle compound (317 mg, 81% yield): mp 181-182° C.; MS (CI/NH₃) m/z 233(M+H)⁺ ; ¹ H NMR (D₂ O, 300 MHz) δ 2.65-2.74 (m, 2H), 4.03-4.21 (m, 2H),4.44 (d, J=4.4 Hz, ¹ H), 4.95 (m, 1H), 7.79 (d, J=2.9 Hz, ¹ H), 8.13 (d,J=2.9 Hz, ¹ H). Anal. Calcd. for C₉ H₁₁ N₂ OCl₂.1.0 HCl: C, 40.10; H,4.11; N, 10.39. Found: C, 39.89; H, 4.08; N, 10.25.

15b. 5-amino-2,3-dichloropyridine

The procedure of Koch and Schnatterer, Synthesis ,1990, 499-501 wasfollowed. To 2-hydroxy-5-nitropyridine (70.0 g, 0.5 mol) in 12 Nhydrochloric acid was added dropwise a solution of potassium chlorate(21.4 g, 0.18 mol) in H₂ O (300 mL) at a rate such that the temperatureremained ≦60° C. The mixture was allowed to stir for a further 30minutes at ca. 50° C., then allowed to cool to ambient temperature, thenwas further cooled in an ice bath. The yellow solid was collected byfiltration, washed with cold H₂ O, and dried under vacuum at 50° C. toafford 3-chloro-2-hydroxy-5-nitropyridine (72.4 g, 83%) as a yellowpowder. To phosphorus oxychloride (37.4 mL, 0.4 mol) at 0° C. was addedquinoline (23.6 mL, 0.2 mol), followed by3-chloro-2-hydroxy-5-nitropyridine (70 g, 0.4 mol) from above. Themixture was heated at 120° C. for 2.5 hours, during which time it becamea dark liquid. After cooling to 100° C., H₂ O (150 mL) was addedcautiously, and the mixture was cooled to 0° C. The precipitated solidwas collected by filtration, washed with cold H₂ O, and dried undervacuum at 50° C. to afford 2,3-dichloro-5-nitropyridine (68.6 g, 89%).To 2,3-dichloro-5-nitropyridine (68.5 g, 0.39 mol) in a mixture of H₂ O(800 mL) and acetic acid (160 mL) were added bits of metallic iron withstirring until the starting material was consumed (TLC analysis). Themixture was filtered, and the filter cake was washed repeatedly withEtOAc. The aqueous filtrate was extracted with EtOAc and the organicfractions were combined and concentrated. The residue waschromatographed (silica gel; MeOH: CHCl₃, 0.5:99.5 to 1:99) to affordthe title compound (44.5 g, 70%) as a light orange powder: MS (CI/NH₃)m/z 163 and 165 (M+H⁺), 180 and 182 (M+NH₄)⁺.

15c. 5-acetoxy-2,3-dichloropyridine

To a flask containing boron trifluoride etherate (11.3 mL, 91.9 mmol) at-15° C. was added dropwise a solution of the compound of Example 15b(10.0 g, 61.3 mmol) in dimethoxyethane (20 mL). Then a solution oft-butyl nitrite (8.7 mL, 73.5 mmol) in dimethoxyethane (61 mL) was addedat such a rate that the internal temperature remained -5° C. The mixturewas stirred at about 5° C. for 0.75 hours, then pentane (200 mL) wasadded. The mixture was filtered and the filter cake was washed with colddiethyl ether, then allowed to dry to afford 15.0 g of a light orangesolid. This material was heated gradually to 70° C. in the presence ofacetic anhydride and held at this temperature until gas evolutionceased, and then for an addition 0.5 hour. The mixture was allowed tocool to ambient temperature, concentrated in vacuo then diluted withdiethyl ether. The solution was washed with H₂ O, then the organic phasewas dried (MgSO₄) and concentrated. The residue was chromatographed(silica gel; ethyl acetate:hexane, 1:9) to afford the title compound(9.2 g, 73%) as a clear yellow oil: MS (CI/NH₃) 206 and 208 (M+H⁺).

15d. 5,6-dichloro-3-pyridinol

The product of Example 15c (9.15 g, 44.4 mmol) was treated with 2 Npotassium hydroxide solution (67 mL, 133 mmol), and the mixture wasstirred for 18 hours. The mixture was diluted with H₂ O and treated withacetic acid to pH 6-7. The solid precipate was collected by filtrationand washed with H₂ O, then dried at 50° C. to afford 5.4 g (94%) of thetitle compound as a white solid: MS (CI/NH₃) 164, 166, 168 (M+H⁺).

Example 16 5-((2R)-azetidinylmethoxy)-2,3-dichloropyridine hydrochloride

Following the procedures of Example 15a, replacing the1-BOC-(2S)-azetidinemethanol thereof with1-t-butyloxycarbonyl-(2R)-azetidinemethanol (3 mmol) (from Step 1d), thetitle compound was prepared (212 mg, 83% yield): mp 166-168° C.; [α]²⁵_(D) 9.5 (c 0.55, MeOH); MS (CI/NH₃) m/z 233, 235, 237 (M+H)⁺ ; ¹ H NMR(D₂ O, 300 MHz) δ 2.65-2.74 (m, 2H), 4.03-4.20 (m, 2H), 4.44 (d, J=4.4Hz, ¹ H), 4.91-5.00 (m, ¹ H), 7.79 (d, J=2.7 Hz, ¹ H), 8.13 (d, J=2.7Hz, ¹ H). Anal. Calcd. for C₉ H₁₁ N₂ OCl₂.1.0 HCl: C, 40.10; H. 4.11; N,10.39. Found: C, 40.01; H, 4.02; N, 10.33.

Example 17 5-((2S)-azetidinylmethoxy)-3-bromo-2-chloropyridinehydrochloride

To a solution of diethyl azodicarboxylate (1.52 mL, 9.6 mmol) in THF (56mL) was added triphenylphosphine (2.52 g, 9.6 mmol) at 0° C., and thereaction mixture was stirred for 0.5 hour.1-t-butyloxycarbonyl-(2S)-azetidinemethanol (1.44 g, 7.7 mmol, Step 7c)and 5-bromo-6-chloropyridin-3-ol (1.4 g, 6.4 mmol; prepared from2-hydroxy-5-nitropyridine according to V. Koch and S. Schnatterer,Synthesis 1990, 499-501) were then added. The reaction mixture wasallowed to warm slowly to room temperature and stirred overnight.Solvent was removed, and the residue was chromatographed (silica gel;chloroform:methanol, 100:1) to afford5-bromo-6-chloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine:MS (CI/NH₃) m/z 377, 379 (M+H)⁺. To a solution of the product from above(360 mg, 0.95 mmol) in methylene chloride at 0° C. was added TFA, andthe mixture was stirred for 30 minutes. The volatile components werethen removed under vacuum. The residue was neutralized with NaHCO₃, thenextracted with methylene chloride, which was dried over MgSO₄ andconcentrated. The residue was chromatographed (silica gel; methylenechloride:methanol:NH₄ OH, 10:1:0.1) to afford to give the free base ofthe title compound. The base was converted to the salt by treatment withhydrogen chloride in ether to give the title compound (224 mg): mp168-169° C.; [α]_(D) ²⁵ -4.81 (c 0.13, MeOH); ¹ H NMR (D₂ O, 300 MHz) δ2.69 (dd, J=7.0, 8.5, 2H), 4.06-4.20 (m, 3H), 4.43 (d, J=4.5, 2H), 4.95(m, ¹ H), 7.94 (d, J=3.0, ¹ H), 8.17 (d, J=3.0, ¹ H); MS (CI/NH₃) m/z277, 279 (M+H)⁺. Anal. Calcd for C₉ H₁₀ N₂ OBrCl.0.9 HCl: C, 34.83; H,3.54; N, 9.03. Found: C, 34.85; H, 3.56; N, 8.82.

Example 18 5-((2R)-azetidinylmethoxy)-3-bromo-2-chloropyridinehydrochloride

A solution of triphenylphosphine (1.10 g, 4.20 mmol) and diethylazodicarboxylate (0.65 mL, 4.2 mmol) in THF (10 mL) was stirred at 0° C.for 0.5 hours followed by addition of a solution containing(R)-azetidinol (0.6 g, 3.2 mmol, from Step 1d above) and5-bromo-6-chloropyridin-3-ol (0.80 g, 3.8 mmol, prepared as described inExample 17) in THF (5 mL). The mixture was warmed to room temperatureover 24 hours, then concentrated. The residue was triturated with amixture of hexane/Et₂ O and filtered to remove the triphenylphosphineoxide. The filtrate was concentrated, and the crude product waschromatographed (silica gel; hexane/EtOAc, 60:40) to give the5-(1-t-butyloxycarbonyl-(2R)-azetidinylmethoxy)-3-bromo-2-chloropyridineas an oil (1.10 g, 91%). The product from above was then dissolved inCH₂ Cl₂ (30 mL) and cooled at 0° C. TFA (excess) was added and themixture was warmed to room temperature over 1 hour. The solution wasthen concentrated, and saturated Na₂ CO₃ solution (30 mL) was addedfollowed by extraction with EtOAc and CH₂ Cl₂. The combined organicextracts were dried (Na₂ SO₄), and concentrated to give the free base ofthe title compound (0.83 g, 100%). A solution containing the free base(0.34 g, 1.2 mmol) was dissolved in CH₂ Cl₂ (10 mL) and cooled to 0° C.followed by dropwise addition of a solution of HCl in Et₂ O until themixture became cloudy. The solvent was removed and the product wasrecrystallized from EtOHlCH₂ Cl₂ /Et₂ O to afford the title compound asa white solid (0.34 g, 81%): mp 175° C; [α]_(D) ²³ 7.2 (c 0.5, MeOH); ¹H NMR (D₂ O, 300 MHz) δ 2.65-2.73 (q, 2H), 4.03-4.20 (m, 2H), 4.43 (d,J=4.2 Hz, 2H), 4.92-4.98 (m, ¹ H), 7.93 (d, J=2.7 Hz, ¹ H), 8.17 (d,J=2.7 Hz, ¹ H); MS (CI/NH₃) m/z: 277 (M+H)⁺ ; Anal. Calcd for C₉ H₁₁ C₁₂BrN₂ O.0.1 H₂ O: C, 34.23; H, 3.57; N, 8.87. Found: C, 34.26; H, 3.36;N, 8.68.

Example 19 5-((2S)-Azetidinylmethyloxy)-2-chloropyridine dihydrochloride

A 950 mg (5.1 mmol) sample of1-t-butyloxycarbonyl-2-(S)-azetidinemethanol, prepared as in Example 7cabove, and 550 mg (4.25 mmol) of 2-chloro-5-hydroxypyridine (Example 1gabove) were added to a solution of triphenylphosphine and DEAD (5.1 mmoleach) in 20 mL of THF, according to the procedure of Example 12a, togive 1.09 g of3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)-6-chloropyridine:[α]_(D) ²⁵ -67.3 (c 1.1, CHCl₃); ¹ H NMR (DMSO-d₆, 300 MHz) δ 8.14 (d,J=3.3 Hz, ¹ H), 7.48 (dd, J=8.8, 3.3 Hz, ¹ H), 7.37 (d, J=8.8 Hz, ¹ H),4.47-4.42 (m, ¹ H), 4.36 (dd, J=11.0, 4.4 Hz, ¹ H), 4.20 (dd, J=11.0,3.3 Hz, ¹ H), 3.77 (t, J=7.7 Hz, 2H), 2.36-2.29 (m, ¹ H), 2.19-2.12 (m,¹ H), 1.36 (s, 9H); MS (CI/NH₃) m/z: 299/301 (M+H)⁺. A portion of thismaterial (1.02 g) was stirred with 10 mL of 4.5 N HCl at roomtemperature for 30 minutes. The solvent was removed, and the residue wasrecrystallized from methanol/ether, to afford 340 mg of the titlecompound: mp 113-115° C.; ¹ H NMR (D₂ O, 300 MHz) δ: 8.15 (d, J=3.0 Hz,¹ H), 7.57 (dd, J=8.9, 3.0 Hz, ¹ H), 7.47 (d, J=8.9 Hz, ¹ H), 4.98-4.89(m, ¹ H), 4.42 (d, J=4.4 Hz, 2H), 4.19-4.02 (m, 2H), 2.68 (q, J=8.5 Hz,2H); MS (CI/NH₃) m/z: 299/301 (M+H)⁺. Anal. Calcd for C₉ H₁₃ N₂ OCl₃ :C, 39.80; H, 4.82; N, 10.32; Found C, 40.12 H, 4.84; N, 10.35.

Example 20 5-((2S)-Azetidinylmethyloxy)-2-methylpyridine dihydrochloride

An ice-cooled solution of the compound from Example 7c (0.232 g, 1.24mmol) was allowed to react with 5-hydroxy-2-methylpyridine (Aldrich,0.142 g, 1.30 mmol) under the conditions of Example 15a, to yield the2-methyl-5-(1-t-butoxycarbonyl-(2S)-azetidinylmethoxy)pyridine (0.123 g,36%) after purification on silica gel (ethyl acetate/hexane 2:1): MS(CI/NH₃) m/z: 279 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ 8.22 (d, J=2.6 Hz,¹ H), 7.20 (dd, J=8.5, 3.0 Hz, ¹ H), 7.08 (d, J=8.5 Hz, ¹ H), 4.50 (m, ¹H), 4.29 (m, ¹ H), 4.13 (dd, J=9.9, 2.9 Hz, ¹ H), 3.89 (t, J=7.75 Hz,2H), 2.51 (s, 3H), 2.37-2.28 (m, 2H), 1.41 (s, 9H). This material (0.12g, 0.44 mmol) was treated with saturated ethanolic HCl (5 mL) for 18 h.The volatiles were removed in vacuo, and the solid was washed with Et₂O, evaporated to dryness and recrystallized (EtOH/Et₂ O) to yield thetitle compound (0.074 g, 63%) as a white solid: mp 141-144° C.; [α]_(D)²⁴ -7.89 (c 0.19, MeOH); MS (CI/NH₃) m/z: 179 (M+H)⁺ ; ¹ H NMR (D₂ O,300 MHz) δ 8.33 (d, J=2.9 Hz, ¹ H), 7.89 (dd, J=9.0, 2.8 Hz, ¹ H), 7.64(d J=8.8 Hz, ¹ H), 4.97 (m, ¹ H), 4.48 (d, J=4.4 Hz, 2H), 4.21-4.04 (m,2H), 2.70 (q, J=8.5 Hz, 2H), 2.62 (s, 3H); Anal. calcd for C₁₀ H₁₆ Cl₂N₂ O.H₂ O: C, 44.62; H, 6.74; N, 10.41. Found: C, 44.55; H, 7.02; N,10.50.

Example 21 5-((2S)-Azetidinylmethyloxy)-3-chloropyridine dihydrochloride

An ice-cooled solution of the compound from Example 7c (0.242 g, 1.20mmol) was allowed to react with 3-chloro-5-hydroxypyridine (0.187 g,1.40 mmol) under the conditions of Example 15a, to afford5-((1-t-butyloxycarbonyl-2-(S)-azetidinyl)methoxy)-3-chloropyridine(0.137 g, 88%) after purification by chormatography (silica gel; ethylacetate/hexane, 2:1): MS (CI/NH₃) m/z: 299 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300MHz) δ 8.25 (d, J=1.38 Hz, ¹ H), 8.21 (br. s, ¹ H), 7.29 (t, J=2.2 Hz, ¹H), 4.52 (m, ¹ H), 4.34 (m, ¹ H), 4.13 (dd, J=10.3, 2.9 Hz, ¹ H),3.91-3.86 (m, 2H), 2.51 (s, 3H), 2.38-2.29 (m, 2H), 1.43 (s, 9H). Aportion of this material (0.13 g, 0.44 mmol) was treated with saturatedethanolic HCl (5 mL) for 16 h. The volatiles were removed in vacuo, andthe solid was recrystallized (EtOH/Et₂ O) to afford the title compound(0.094 g, 80%) as a white solid: mp 156-157° C.; [α]_(D) ²³ -3.23 (c0.16, MeOH); MS (CI/NH₃) m/z: 199 (M+H)⁺, 216 (M+NH₄)⁺ ; ¹ H NMR (D₂ O,300 MHz) δ 8.41 (d, J=5.1 Hz, ¹ H), 8.39 (d, J=4.4 Hz, ¹ H), 7.94 (t,J=2.1 Hz, ¹ H), 4.97 (m, ¹ H), 4.50 (d, J=4.0 Hz, 2H), 4.20-4.03 (m,2H), 2.69 (q, J=8.45 Hz, 2H); Anal. calcd for C₉ H₁₃ Cl₃ N₂ O.0.5 H₂ O:C, 38.53; H, 5.03; N, 9.98. Found: C, 38.51; H, 5.16 N, 9.96.

Example 22 5-Vinyl-3-((2S)-Azetidinylmethyloxy)1pyridine dihydrochloride

5-Bromo-3-(2-(1-t-butyloxycarbonyl-2-(S)-azetidinyl)methoxy)pyridine(1.37 g, 3.99 mmol, Step 12a above) in toluene (30 mL) was mixed withvinyltributyltin (1.44 mL, 4.79 mmol, Aldrich),tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.200 mmol). Themixture was stirred at 100° C. overnight, cooled to ambient temperature,then the volatile components were removed in vacuo. Purification bychromatography (silica gel; hexane/EtOAc, 5:1 to 1:1) afforded thevinyl-substituted pyridine as an oil (1.06 g, 92%): MS (CI/NH₃) m/z: 291(M+H)⁺ ; ¹ H NMR (CDCl₃, 300MHz) δ 1.40 (s, 9H), 2.30-2.42 (m, 2H), 3.87(t, J=7.72 Hz, 2H), 4.11 (dd, J=2.94, 9.92 Hz, ¹ H), 4.35 (m, ¹ H), 4.53(m, ¹ H), 5.80 (d, J=12.67 Hz, ¹ H), 5.83 (d, J=19.33 Hz, ¹ H), 6.68(dd, J=12.67, 19.33 Hz, ¹ H), 7.29 (t, J=2.67 Hz, ¹ H), 8.24 (d, J=3.30Hz, ¹ H). A portion of this material (191 mg, 0.66 mmol) was dissolvedin CH₂ Cl₂ (2 mL) at 0° C. and TFA (1.8 mL) was added. After stirringfor 30 min, the solution was basified with 15% aqueous NaOH andextracted with CH₂ Cl₂. The combined organic extracts were dried overMgSO₄ and concentrated. Purification by chromatography (silica gel; CH₂Cl₂ /MeOH/NH₄ OH, 10:0.4 to 10:1:0.3) afforded the free amine of thetitle compound as an oil (101 mg, 81%)L: MS (CI/NH₃) m/z: 191 (M+H)⁺ ; ¹H NMR (CDCl₃, 300 MHz) δ 2.44-2.56 (m, 2H), 3.72 (m, ¹ H ), 3.88 (m, ¹H), 4.16 (m, 2H), 4.54 (m, ¹ H), 5.40 (d, J=11.03 Hz, ¹ H), 5.82 (d,J=17.65 Hz, ¹ H), 6.66 (dd, J=11.0, 17.65 Hz, ¹ H), 7.26 (m, ¹ H), 8.18(d, J=3.33 Hz, ¹ H), 8.22 (d, J=1.67 Hz, ¹ H). The amine was slurried inEt₂ O and a solution of 1.0 M HCl in Et₂ O was added dropwise. Thesolvent was removed and the product was recrystallized from MeOH/Et₂ Oto afford a the title compound a yellow hygroscopic powder: mp 88-90°C.; [α]_(D) ²³ +2.58° (c 0.62, MeOH); MS (CI/NH₃) m/z: 191 (M+H+)⁺ ; ¹ HNMR (D₂ O, 300 MHz) δ 2.64-2.76 (m, 2H), 4.04-4.20 (m, 2H), 4.49 (d,J=4.1 Hz, 2H), 4.96 (m, ¹ H), 5.58 (d, J=11.0 Hz, ¹ H), 6.04 (d, J=17.7Hz, ¹ H), 6.83 (dd, J=11.0 Hz, J=17.7 Hz, ¹ H), 7.85 (t, J=1.9 Hz,1H),8.33 (d, J=14.3 Hz, ¹ H); Anal. Calcd for C₁₁ H₁₄ N₂ O.1.8 HCl: C,51.64; H, 6.22; N, 10.95. Found: C, 51.59; H, 5.92; N, 10.75.

Example 23 5-Ethyl-3-((2S)-Azetidinylmethyloxy)lpyridine hydrochloride

5-(N-t-Butyloxycarbonyl-(2S)-azetidinylmethoxy)-3-bromopyridine (1.37 g,3.99 mmol, Example 12a above) in toluene (30 mL) was mixed withvinyltributyltin (1.44 mL, 4.79 mmol),tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.20 mmol). Thereaction mixture was stirred at 100° C. for 16 hours. Solvent wasremoved under reduced pressure and the resultant residue waschromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford3-vinyl-5-(N-t-butyloxycarbonyl-(S)-azetidinyl-2-methoxy)pyridine as anoil (1.06 g, 92%): MS (CI/NH₃) m/z: 291(M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz)δ 1.40 (s, 9H), 2.30-2.42 (m, 2H), 3.87 (t, J=7.7 Hz, 2H), 4.11 (dd,J=2.9, 9.9 Hz, ¹ H), 4.35 (m, ¹ H), 4.53 (m, ¹ H), 5.80 (d, J=12.7 Hz, ¹H), 5.83 (d, J=19.3 Hz, ¹ H), 6.68 (dd, J=12.6, 19.3 Hz, ¹ H), 7.29 (t,J=2.7 Hz, ¹ H), 8.24 (d, J=3.3 Hz, ¹ H). A suspension of 5% Pt on carbon(54 mg, Aldrich) and3-vinyl-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (540 mg,1.87 mmol) in MeOH (10 mL) at room temperature was placed under anatmosphere of hydrogen for 16 h. Removal of the catalyst by filtrationand concentration of the solvent afforded3-ethyl-5-(N-t-butyloxycarbonyl-(2S)-azetidinyl-2-methoxy)pyridine as anoil (480 mg, 88%): MS (CI/NH₃) m/z: 293 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300MHz) δ 1.25 (t, J=8.3 Hz, 3H), 1.42 (s, 9H), 2.20-2.40 (m, 2H), 2.64)q,J=8.3 Hz, 2H), 3.88 (t, J=8.3 Hz, 2H), 4.12 (dd, J=3.3, 8.0 Hz, ¹ H),4.32 (m, ¹ H), 4.51 (m, ¹ H), 7.08 (t, J=3.3 Hz, ¹ H), 8.08 (d, J=1.7Hz, ¹ H), 8.16 (d, J=2.3 Hz, ¹ H). To a solution of the product fromabove (479 mg, 1.64 mmol) in CH₂ Cl₂ (6 mL) at 0° C. was added TFA (5.5mL). After 30 min the solution was basified with 15% aqueous NaOH andextracted with CH₂ Cl₂ (3×). The organic extract was dried over MgSO₄,filtered and concentrated. Purification by chromatography (silica gel;CH₂ Cl₂ /MeOH/NH₄ OH, 10:0.4:0 to 10:1:0.3) afforded the free base ofthe title compound as an oil (228 mg, 72%): MS (CI/NH₃) m/z: 193 (M+H)⁺; ¹ H NMR (CDCl₃, 300 MHz) δ 1.24 (t, J=8.3 Hz, 3H), 2.20-2.48 (m, 2H),2.62 (q, J=8.3 Hz, 2H), 3.46-3.54 (m, 2H), 3.64 (q, J=8.7 Hz, ¹ H), 4.06(t, J=5.7 Hz, 2H), 7.16 (t, J=2.7 Hz, ¹ H), 8.07 (d, J=1.7 Hz, ¹ H),8.13 (d, J=3.3 Hz, ¹ H). The free amine was dissolved in Et₂ O and HClin Et₂ O was added dropwise carefully. The solvent was then removed, andthe salt was recrystallized from MeOH/Et₂ O to afford a the titlecompound as a white hygroscopic solid: [α]_(D) ²⁵ +3.85° (c 3.64, MeOH);MS (CI/NH₃) m/z: 193 (M+H)⁺ ; ¹ H NMR (D₂ O, 300 MHz) δ 1.23 (t, J=7.8Hz, 3H), 3.84-3.90 (m, 3H), 4.37 (dd, J=3.4, 11.2 Hz, 2H), 4.54 (dd,J=7.5, 11.2 Hz, ¹ H), 4.64-4.60 (m, 2H), 4.92 (m, ¹ H), 7.62 (s, ¹ H),8.26(s, ¹ H). Anal. Calcd for C₁₁ H₁₆ N₂ 0.1.8 HCl: C, 51.23; H, 6.96;N, 10.86. Found: C, 51.03; H, 6.70; N, 10.96.

Example 24 5-Propyl-3-((2S)-azetidinylmethyloxy)1pyridine hydrochloride

To a solution of5-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)-3-bromopyridine (1.50 g,4.37 mmol, Example 12a above) in THF (30 mL) at 0° C. was added[1,3-bis(diphenylphosphino)-propane]nickel(II) (14.0 mg) followed bypropylmagnesium chloride (5.50 mL of a 2 M solution in diethyl ether,Aldrich). The reaction mixture was refluxed for 3 h, cooled to ambienttemperature and then quenched with saturated aqueous ammonia chloride.The desired product was extracted with CH₂ Cl₂. The organic phase wasdried over MgSO₄, filtered and concentrated. The residue waschromatographed (silica gel; hexane/EtOAc, 10:1 to 1:1) to afford5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine as anoil (292 mg, 22%): MS (CI/NH₃) mn/z: 307 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300MHz) δ 0.95 (t, J=8.3 Hz, 3H), 1.42 (s, 4.5H), 1.46 (s, 4.5H), 1.60-1.70(m, 2H), 2.22-2.40 (m, 2H), 2.56 (t, J=8.3 Hz, 2H), 3.70-3.80 (m, 2H),3.90(m, ¹ H), 4.13 (m, ¹ H), 4.51 (m, ¹ H), 7.04 (s, ¹ H), 8.06 (s, ¹H), 8.18 (d, J=3.3 Hz, ¹ H). To a 0° C. solution of5-propyl-3-(N-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (290mg, 0.950 mmol) in CH₂ Cl₂ (3 mL) was added TFA (3 mL). After stirringfor 30 min the reaction mixture was basified with 15% aqueous NaOH andextracted with CH₂ Cl₂ (3×). The combined organic extracts were driedover MgSO₄, filtered and concentrated. Purification by chromatography(silica gel; CH₂ Cl₂ /MeOH, 10:0.5) afforded the free base of the titlecompound as an oil (103 mg, 53%): MS (CI/NH₃) m/z: 207 (M+H)⁺ ; ¹ H NMR(CDCl₃, 300 MHz) δ 0.94 (t, J=8.3 Hz, 3H), 1.58-1.70 (m, 2H), 2.30-2.48(m, 2H), 2.55 (t, J=8.3 Hz, 2H), 3.57 (m, ¹ H), 3.76 (q, J=8.3 Hz, ¹ H),4.04-4.10 (m, 2H), 4.39 (m, ¹ H), 7.03 (t, J=3.0 Hz, ¹ H), 8.04 (s, ¹H), 8.14 (d, J=3.3 Hz, ¹ H). The free base was dissolved in Et₂ O and asaturated solution of HCl in Et₂ O was added dropwise carefully. Thesolvent was removed, and the resultant solid was recrystallized fromMeOH/Et₂ O to afford the title compound as a yellow hygroscopic solid:mp 79-80° C.; MS (CI/NH₃) m/z: 207 (M+H)⁺ ; ¹ H NMR (D₂ O, 300 MHz) δ1.01 (t, J=3.05 Hz, 3H), 1.68-1.80 (m, 2H), 2.62-2.78 (m, 2H), 2.80 (t,J=7.1 Hz, 2H), 4.04-4.21 (m, 3H), 4.44-4.60 (m, 2H), 7.40 (s, ¹ H), 8.04(s, ¹ H), 8.14 (s, ¹ H). Anal. Calcd for C₁₂ H₁₈ N₂ O.2 HCl.H₂ O: C,48.49; H, 7.46; N, 9.43. Found: C, 48.35; H, 7.23; N, 9.48.

Example 25 2-Chloro-3-methyl-5-(2-(S)-azetidinylmethoxy)pyridine citrate

25a. 2-Chloro-3-methyl-5-(2-(S)-azetidinylmethoxy)pyridine citrate

To a solution of triphenylphosphine (0.55 g, 2.09 mmol) and(S)-1-t-butyloxycarbonyl-2-azetidinemethanol (0.39 g, 2.09 mmol, Example7c) in THF (5 mL) at 0° C. was added 2-chloro-3-methyl-5-hydroxypyridine(0.20 g, 1.39 mmol, Step 25b below). The mixture was allowed to warm toambient temperature, then diethyl azodicarboxylate (0.33 mL, 2.09 mmol)was added dropwise, and the mixture was stirred for 16 hours. Thesolvent was removed in vacuo, and the residue was diluted with hexaneand sonicated for 30 minutes. The resulting precipitate was separated byfiltration and washed with hexane. The hexane was removed in vacuo andthe residue was chromatographed (silica gel; hexane/EtOAc, 1:1) to givea product that was contaminated with triphenylphosphine oxide.

To a solution of the product from above in methylene chloride (6 mL) at0° C. was added trifluoroacetic acid (6 mL). The mixture was stirred at0° C. for 40 minutes then allowed to warm to room temperature and stirfor an additional 30 minutes. Then saturated K₂ CO₃ was added and themixture was extracted with CH₂ Cl ₂. The organic layer was then dried(MgSO₄) and concentrated. The residue was purified (silica gel; 1% NH₄OH/10% MeOH/EtOAc) to give 0.12g (27%) of2-chloro-3-methyl-5-(2S)-pyrrolidinylmethoxy)pyridine as a pale yellowoil: MS (CI/NH₃) m/z: 213 (M +H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ 2.34 (s,3H), 2.34-2.55 (m, 2H), 3.64 (m, ¹ H), 3.84 (q, J=9 Hz, ¹ H), 4.03-4.98(m, 2H), 4.45 (m, ¹ H), 7.16 (d, J=3.0 Hz, ¹ H), 7.93 (d, J=3.0 Hz, ¹H).

The product from above was dissolved in ethanol and treated with citricacid (108 mg) in ethanol. The solvent was removed in vacuo. Theresulting salt was triturated with diethyl ether and dried under vacuumto give a white powder: mp 125-127° C.; [α]_(D) ²⁵ -4.2 (c 1.0, MeOH);MS (CI/NH₃) m/z: 213 (M+H)⁺ ; ¹ H NMR (D₂ O, 300 MHz) δ: 2.27 (d, J=10.5Hz, ¹ H), 2.36 (s, 3H), 2.41-2.91 (m, 8H), 4.0-4.21 (m, 2H), 4.40 (d,J=5 Hz, ¹ H), 4.93 (m, ¹ H), 7.48 (d, J=3.1 Hz, ¹ H), 7.97 (d, J=3.0 Hz,¹ H). Anal. Calcd for C₁₀ H₁₃ N₂ OCI. 1.2 C₆ H₈ O₇. H₂ O: C, 44.79; H,5.38; N, 6.07. Found 5.29; N, 5.91.

25b. 2-chloro-3-methyl-5-hydroxypyridine

2-Chloro-3-methyl-5-nitropyridine (3.2 g, 18.5 mmol; Maybridge ChemicalCo.) was dissolved in a mechanically stirred solution of H₂ O/HOAc (60mL, 5:1). Iron powder was added over a 5 h period, maintaining thetemperature below 40° C., and stirring was continued until startingmaterial had be consumed. The reaction mixture was filtered, and thefilter cake was washed with EtOAc. The aqueous filtrate was extractedwith EtOAc, and the combined organic fractions were washed withsaturated NaHCO₃ solution, dried (MgSO₄) and concentrated. The residuewas chromatographed (silica gel; CHCl₃ /MeOH, 98:2) to afford5-amino-2-chloro-3-methylpyridine as an orange solid (2.34 g, 89%): MS(CI/NH₃) m/z: 143 (M+H)⁺ ; NMR (DMSO-d₆, 300 MHz) δ 2.17 (s, 3H), 5.40(br s, 2H), 6.90 (d, J=2.2 Hz, ¹ H), 7.54 (d, J=2.2 Hz, ¹ H).

To a solution of boron trifluoride diethyl etherate (5.8 mL, 47.5 nmmol)in DME (18 mL) at -14° C. was added dropwise a solution of5-amino-2-chloro-3-methylpyridine (4.5 g, 31.7 mmol) in DME (60 mL). Themixture was stirred for 15 minutes and then a solution of t-butylnitrite (4.5 mL, 38 mmol) in DME (60 mL) was added dropwise. The mixturewas stirred for 1 hour at 0° C., then pentane (100 mL) was added to givea solid. The solid was collected by filtration and dried to give thetitle compound (6.9 g): ¹ H NMR (MeOH-d₄, 300 MHz) δ 2.58 (s, 3H), 8.86(d, J=2.1 Hz, ¹ H), 9.41 (d, J=2.4 Hz, ¹ H).

A solution of the above solid (2.49 g) in acetic anhydride (20 mL) washeated at 70° C. for 4 hours. The solvent was then evaporated underreduced pressure and H₂ O (200 mL) was added. The solution was adjustedto pH 9 with solid K₂ CO₃ following by extraction with EtOAc. Theorganic layer was then washed with H₂ O and brine, dried (Na₂ SO₄), andconcentrated. The residue was chromatographed (silica gel; hexane/EtOAc,50:50) to give 5-acetoxy-2-chloro-3-methylpyridine as an oil (1.45 g,76%): ¹ H NMR (CDCl₃, 300 MHz) δ 2.32 (s, 3H), 2.39 (s, 3H), 7.37 (dd,J=1.5, 1.5 Hz, ¹ H), 8.06 (d, J=2.7, ¹ H); MS (CI/NH₃) m/z 186 (M+H)⁺,203 (M+NH₄)⁺.

The acetate obtained above (1.25 g, 6.7 mmol) was hydrolyzed with 2 Naqueous potassium hydroxide solution. The solution was adjusted to pH6.0 with acetic acid followed by extraction with ethyl acetate. Theorganic layer was washed with H₂ O and brine, dried (MgSO₄), andconcentrated. The residue was chromatographed (silica gel; hexane/EtOAc,50:50) to give the title compound as an oil (1.2 g, 100%): ¹ H NMR(CDCl₃, 300 MHz) δ 2.36(s, 3H), 7.19 (d, J=3.0 Hz, ¹ H), 7.89 (d, J=3.0Hz, ¹ H); MS (CI/NH₃) m/z 144 (M+H)⁺, 146 (M+3H)⁺, 161(M+H+NH4)⁺,163(M+2H+NH4)⁺.

Example 26 2-Chloro-3-vinyl-5-((2S)-azetidinylmethoxy)pyridinehydrochloride

To5-bromo-6-chloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridinefromExample 17 above (1.00 g, 2.65 mmol) in toluene (30 mL) was addedtetrakis(triphenylphosphine) palladium(0) (93 mg, 0.081 mmol) andvinyltributyltin (0.93 mL, 3.18 mmol). The mixture heated at 95° C.overnight, then the volatile components were removed in vacuo. Theresidue was chromatographed (silica gel; CH₂ Cl₂ /MeOH, 100:2) to afford2-chloro-3-vinyl-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridineas an oil (720 mg, 84%): ¹ H NMR (CDCl₃, 300 MHz) δ 1.42 (s, 9H), 2.33(m, 2H), 3.89 (t, J=8.5 Hz, 2H), 4.14 (m, ¹ H), 4.36 (m, ¹ H), 4.52 (m,¹ H), 5.50 (d, J=10.9 Hz, ¹ H), 5.80 (d, J=17 Hz, ¹ H), 6.98 (dd, J=17.6Hz, J=11.2 Hz, ¹ H), 7.44 (d, J=2.7 Hz, ¹ H), 8.02 (d, J=2.7 Hz, ¹ H);MS (CI/NH₃) m/z: 325 (M+H)⁺. This product was treated with TFA in CH₂Cl₂ to give, following extractive work-up, the free base of the titlecompound. The free amine was converted to the hydrochloride salt bytreatment with a solution of HCl in diethyl ether to give the titlecompound as a light yellow hygroscopic solid: mp 121° C. (dec); MS(CI/NH₃): m/z 225 (M+H⁺), 242 (M+NH₄ ⁺). Anal. Calcd for C₁₁ H₁₃ ClN₂O.1.1 HCl: C, 49.90; H, 5.37; N, 10.58. Found: C, 49.84; H, 5.25; N,10.27.

Example 27 2-Chloro-3-ethyl-5-((2S)-azetidinylmethoxy)pyridinehydrochloride

A suspension of 5% Pt on carbon and2-chloro-3-vinyl-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine(Example 26 above, 440 mg, 1.36 mmol) in MeOH (10 mL) were stirredovernight under an atmosphere of hydrogen (balloon). The mixture wasfiltered and the filtrate was concentrated to afford2-chloro-3-ethyl-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridineas a colorless oil (219 mg, 51%): ¹ H NMR (CDCl₃, 300 MHz) δ 1.25 (t,J=7.5 Hz, 3H), 1.42 (s, 9H), 2.32 (m, 2H), 2.71 (q, J=7.5 Hz, 2H), 3.89(t, J=7.8 Hz, 2H), 4.12 (dd, J=3.0, 9.8 Hz, 1H), 4.30 (m, ¹ H), 4.50 (m,1H), 7.16 (d, J=3.1 Hz, 1H), 7.94 (d, J=3.0 Hz, 1H); MS (CI/NH₃) m/z 327(M+H)⁺. To a solution of the product from above (216 mg, 0.66 mmol) inCH₂ Cl₂ (2 mL) at 0° C. was added trifluoroacetic acid (1.8 miL). Thesolution was allowed to warm to room temperature, then adjusted to pH 11with aqueous 10% NaOH, and extracted with CH₂ Cl₂. The organic extractwas dried over MgSO₄ and concentrated. The residue was chromatographed(silica gel; CH₂ Cl₂ /MeOH, 100:3 to 100:15) to afford the free base ofthe title compound as an oil (60 mg, 40%): ¹ H NMR (CDCl₃, 300 MHz) δ1.22 (m 3H), 2.38 (m, 2H), 2.71 (q, J=7.5 Hz, 2H), 3.57 (m, 1H), 3.80(m, 1H), 4.08 (m, 2H), 4.38 (m, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.92 (d,J=3.0 Hz, 1H); MS (CI/NH₃) m/z: 227 (M+H)⁺. The free base was dissolvedin THF and treated with 1 M HCl in Et₂ O to afford the hydrochloridesalt, which was triturated with Et₂ O and dried under vacuum to affordthe title compound as a white solid: mp 102-104° C.; [α]_(D) ²³ -9.68 (c0.62, MeOH); ¹ H NMR (D₂ O) δ 1.24 (t, J=7.5 Hz, 3H), 2.71 (m, 4H), 4.11(m, 2H), 4.42 (d, J=4 Hz, 2H), 4.95 (m, 1H), 7.51 (d, J=3 Hz, 1H), 8.00(d, J=3 Hz, 1H). Anal. Calcd. for C₁₁ H₁₅ N₂ OCl.1.1 HCl: C, 49.52; H,6.08; N, 10.50. Found: C, 49.63; H, 5.89; N, 10.20.

Example 28 2-Chloro-3-propyl-5-((2S)-azetidinylmethoxy)pyridinehydrochloride

2-Chloro-3-bromo-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine(1.20 g, 3.18 mmol, from Example 17 above) in toluene (10 mL) was mixedwith allyltributyltin (1.98 mL, 6.36 mmol) andtetrakis(triphenylphosphine)palladium(0) (305 mg). The reaction mixturewas stirred at 100° C. for 16 hours. The solvent was removed undervacuum and the resultant residue was chromatographed (silica gel;hexane/EtOAc, 5:1) to afford2-chloro-3-(3-propenyl)-5-(1-t-butyloxycarbonyl-(S)-azetidinyl-2-methoxy)pyridineas an oil (947 mg, 88%): MS (CI/NH₃) m/z: 339 (M+H)⁺ ; ¹ H NMR (CDCl₃,300 MHz) δ 1.40 (s, 9H), 2.20-2.40 (m, 2H), 3.45 (d, J=6.60 Hz, 2H),3.89 (t, J=7.72 Hz, 2H), 4.11 (dd, J=2.94, 9.92 Hz, ¹ H), 4.30 (m, ¹ H),4.51 (m, ¹ H), 5.10-5.20 (m, 2H), 5.93 (m, ¹ H), 7.17 (d, J=2.94 Hz, ¹H), 7.98 (d, J=3.31 Hz, ¹ H). A suspension of the product above (945 mg,2.79 mmol) and 5% Pt on carbon (500 mg) in MeOH (10 mL) were stirredunder an atmosphere of hydrogen for 16 hours. The catalyst was filteredand the solvent was removed in vacuo to afford the desired product (770mg, 81%) as an oil. MS (CI/NH₃) m/z: 341 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300MHz): δ 0.99 (t, J=7.5 Hz, 3H), 1.42 (s, 9H), 1.60-1.74 (m, 2H),2.20-2.40 (m, 2H), 2.65 (t, J=7.5 Hz, 2), 3.89 (t, J=7.5 Hz, 2H), 4.11(dd, J=3.1, 9.8 Hz, 1H), 4.32 (m, 1H), 4.50 (m, 1H), 7.14 (d, J=2.7 Hz,1H), 7.95 (d, J=3.1 Hz, 1H,). The product from above (759 mg, 2.22 mmol)was dissolved in CH₂ Cl₂ (4 mL) and TFA (3 mL) was added at 0° C. Afterstirring for 30 min, the reaction was warmed to room temperature slowly.The reaction mixture was then basified with 15% aqueous NaOH andextracted with CH₂ Cl₂. The combined organic extracts were dried overMgSO₄, filtered and concentrated. The crude product was chromatographed(silica gel; CH₂ Cl₂ /MeOH, 10:0.4 to 10:1:0.3 CH₂ Cl₂ /MeOH/NH₄ OH) toafford the free base of the title compound as an oil (193 mg, 50%): MS(CI/NH₃) m/z: 241 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ 0.98 (t, J=7.35Hz, 3H), 1.58-1.70 (m, 2H), 2.60-2.70 (m, 4H), 3.96-4.10 (m, 2H),4.24-4.32 (m, 2H), 4.79 (m, 1H), 7.16 (d, J=3.4 Hz, 1H), 7.91 (d, J=2.9Hz, 1H). The free base from above was dissolved in Et₂ O and HCl in Et₂O was added dropwise. The solvent was removed and the productrecrystallized from MeOH/Et₂ O to afford a white hygroscopic solid: mp148-150° C.; [α]_(D) -8.54 (c 2.67, MeOH); MS (CI/NH₃) m/z: 241 (M+H)⁺ ;¹ H NMR (D₂ O, 300 MHz) δ 0.95 (t, J=7.1 Hz, 3H), 1.60-1.74 (m, 2H),2.71 (t, J=8.1 Hz, 4H), 4.04-4.22 (m, 2H), 4.41 (d, J=4.1 Hz, 2H), 4.97(m, 1H), 7.48 (d, J=3.1 Hz, ¹ H), 8.00 (d, J=3.1 Hz, ¹ H); Anal. Calcdfor C₁₂ H₁₇ N₂ OCl.1.6 HCl.0.1 H₂ O: C, 47.90; H, 6.30; N, 9.31. Found:C, 47.97; H, 5.91; N, 9.14.

Example 29 3-Butyl-2-chloro-5-((2S)-azetidinylmethoxy)pyridinehydrochloride

2-Chloro-3-bromo-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)-pyridine(1.00 g, 2.70 mmol, from Step 17 above) in toluene (10 mL) was addedPd(OAc)₂ (67 mg, Aldrich) and tri-o-tolylphoshine (335 mg, Aldrich).1-Butene was bubbled through the mixture for 20 minutes. The reactionmixture was stirred at 100° C. in sealed tube for 16 hours, cooled toambient temperature, then the volatile components were removed underreduced pressure. The residue was chromatographed (silica gel;hexane/EtOAc, 5:1 to 2:1) to afford an oil (715 mg, 76%): MS (CI/NH₃)m/z: 353 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ 1.13 (t, J=7.4 Hz, 3H) 1.42(s, 9H), 2.20-2.50 (m, 4H), 3.89 (t, J=7.7 Hz, 2H), 4.09 (m, 1H), 4.28(m, 1H), 5.00 (m, 1H), 5.54 (m, 1H), 7.14 (d, J=2.9 Hz, 1H), 7.96 (d,J=3.0 Hz, 1H). A suspension of the 2-chloro-3-butenylpyridine from above(420 mg, 1.19 mmol) and 5% Pt on carbon (40 mg) in MeOH (10 mL) wasplaced under an atmosphere of hydrogen (balloon) for 16 hours. Thecatalyst was filtered and the solvent was removed in vacuo to afford thedesired product (310 mg, 74%): MS (CI/NH₃) m/z: 355 (M+H)⁺ ; ¹ H NMR(CDCl₃, 300 MHz) δ 0.96(t, J=7.5 Hz, 3H), 1.42 (s, 9H), 1.56-1.60 (m,4H), 2.22-2.40 (m, 2H), 2.67 (t, J=7.8 Hz, 2H), 3.84-3.94 (m, 2H), 4.12(m, 1H), 4.32 (m, 1H), 4.50 (m, 1H), 7.14 (d, J=7.1 Hz, 1H), 7.94 (t,J=7.1 Hz, 1H). The product from above (310 mg, 0.87 mmol) was dissolvedin CH₂ Cl₂ (2 mL) at 0° C. and TFA (1.2 mL) was added. After stirringfor 30 min, the reaction mixture was basified with 15% aqueous NaOH andextracted with CH₂ Cl₂. The combined organic extracts were dried overMgSO₄, filtered and concentrated. The crude product was chromatographed(silica gel; CH₂ Cl₂ /MeOH/NH₄ OH, 10:0.4:0 to 10:1:0.3) to afford thefree base of the title compound as an oil (165 mg, 75%): MS (CI/NH₃)m/z: 255 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ 0.95 (t, J=7.1 Hz, 3H),1.32-1.44 (m, 2H), 2.54-2.66 (m, 4H), 2.38-2.56 (m, 2H), 2.67 (t, J=7.8Hz, 2H), 3.67 (m, 1H), 3.86 (m, 1H), 4.044.20 (m, 2H), 4.49 (m, 1H),7.15 (d, J=3.1 Hz, 1H), 7.91 (d, J=2.7 Hz, 1H). The free base wasdissolved in Et₂ O and HCl in Et₂ O was added dropwise carefully. Thesolvent was removed and the resultant salt was recrystallized fromMeOH/Et₂ O to afford the title compound as a white solid: mp. 88-90° C.;[α]_(D) -8.00 (c 1.92, MeOH); MS (CI/NH₃) m/z: 255 (M+H)⁺ ; ¹ H NMR (D₂O, 300 MHz) δ 0.93 (t, J=7.3 Hz, 3H), 1.35-1.42 (m, 2H), 1.58-1.68 (m,2H), 2.60-2.78 (m, 4H), 4.02-4.22 (m, 2H), 4.41 (d, J=4.1 Hz, 2H), 4.97(m, 1H), 7.50 (s, 1H), 8.00 (d, J=2.6 Hz, 1H). Anal. Calcd for C₁₃ H₁₉N₂ OCl.1.5 HCl.0.1 H₂ O: C, 50.17; H, 6.70; N, 9.00. Found: C, 50.27; H,6.95; N, 8.89.

Example 30 2-Chloro-3-ethynyl-5-((2S)-azetidinylmethoxy)pyridinehydrochloride

2-Chloro-3-bromo-5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine(1.00 g, 2.65 mmol, from Step 17 above) was mixed withtrimethylsilylacetylene (0.45 mL, 3.18 mmol),tetrakis(triphenylphosphine)palladium(0) (305 mg), copper(I) iodide (50mg) and triethylamine (1 mL) in toluene (20 mL). The reaction mixturewas stirred at 100° C. for 16 hours. The solvent was removed and theresidue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 2:1) toafford the trimethylsilylethynyl-substituted pyridine as an oil (770 mg,74%): MS (CI/NH₃) m/z: 395 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ 1.43 (s,9H), 2.20-2.40 (m, 2H), 3.80-3.92 (m, 2H), 4.12 (m, ¹ H), 4.32 (m, ¹ H),4.49 (m, ¹ H), 7.38 (d, J=3.1 Hz, ¹ H), 8.05 (d, J=3.0 Hz, ¹ H). SolidK₂ CO₃ (293 mg, 2.12 mmol) was added to a solution of the product fromabove (760 mg, 1.93 mmol) in MeOH (20 mL). The reaction mixture wasstirred at ambient temperature for 2 hours, then diluted with EtOAc andwashed with H₂ O. The organic layer was dried over MgSO₄ andconcentrated to afford the ethynyl-substituted pyridine (610 mg, 98%):MS (CI/NH₃) m/z: 323 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ 1.42 (s, 9H),2.20-2.40 (m, 2H), 3.46 (s, 1H), 3.84-3.92 (m, 2H), 4.07 (m, 1H), 4.33(m, 1H), 4.52 (m, 1H), 7.41 (d, J=2.9 Hz, 1H), 8.08 (d, J=2.9 Hz, 1H).The product from above (605 mg, 1.88 mmol) was dissolved in CH₂ Cl₂ (2mL) and TFA (2 mL) was added at 0° C. After stirring for half hour, thereaction was warmed to room temperature slowly. Then the mixture wasbasified with 15% aqueous NaOH and extracted with CH₂ Cl₂. The combinedorganic extracts were dried over MgSO₄ and concentrated. The crudeproduct was chromatographed (silica gel; CH₂ Cl₂ /MeOH/NH₄ OH, 10:0.4:0to 10:1:0.3) to afford the free base of the title compound as an oil(265 mg, 64%): MS (CI/NH3) m/z: 223 (M+H)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ2.20-2.40 (m, 2H), 3.45 (m, 1H), 3.74 (m, 1H), 3.98-4.06 (m, 2H), 4.25(m, 1H), 7.38 (d, J=2.9 Hz, 1H), 8.08 (d, J=3.0 Hz, 1H). The free basefrom above was dissolved in Et₂ O and HCl in Et₂ O was added dropwisecarefully. The solvent was removed and the product recrystallized fromMeOH/Et₂ O to afford a brown hygroscopic solid: mp. 90° C. (dec.); MS(CI/NH₃) m/z: 223 (M+H)⁺ ; ¹ H NMR (D₂ O, 300 MHz) δ 2.71 (q, J=8.2 Hz,2H), 4.04-4.22 (m, 2H), 4.44 (d, J=4.1 Hz, 2H), 4.92-5.00 (m, 1H), 7.77(d, J=3.5 Hz, 1H), 8.19 (d, J=3.1 Hz, 1H). Anal.Calcd for C₁₁ H₁₁ N₂OCl.1.1 HCl.0.5 H₂ O: C, 48.60; H, 4.63; N, 10.30. Found: C, 48.70; H,4.81; N, 10.01.

Example 31 5-((2S)-azetidinylmethoxy)-3-bromo-2-fluoropyridine dibenzoicacid salt

31a. 5-((2S)-azetidinylmethoxy)-3-bromo-2-fluoropyridine dibenzoate

To a solution of diethyl azodicarboxylate (0.7 mL, 4.4 mmol) in THF (25mL) was added triphenylphosphine (1.19 g, 4.4 mmol) at 0° C., and thereaction mixture was stirred for 0.5 hour.1-t-Butyloxycarbonyl-(2S)-azetidinemethanol (0.85 g, 4.5 mmol, Example7c) and 5-bromo-6-fluoropyridin-3-ol (0.75 g, 4.0 mmol, Step 31d) werethen added. The reaction mixture was allowed to warm slowly to roomtemperature and stirred overnight. The solvent was removed, and theresidue was chromatographed (silica gel, hexane/ethyl acetate, 5:1) toafford5-bromo-6-fluoro-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine(1.02 g, 72.3%): MS (CI/NH₃) m/z 362, 379 (M+H)⁺, (M+NH₄ ⁺); ¹ H NMR(CDCl₃ 300 MHz) δ 7.82 (m, 1H), 7.60 (dd, J=3.1, 7.1 Hz 1H), 4.51 (m,1H), 4.35 (m, 1H), 4.11 (dd, J=3.1, 10.2 Hz, 1H), 3.88 (m, 2H), 2.33 (m,2H), 1.45 (s, 9H). To a solution of the product from above (0.70 g, 1.9mmol) in CH₂ Cl₂ (2 mL) at 0° C. was added TFA (2 mL). After 30 min thevolatile components were removed under vacuum, the residue was dilutedwith saturated aqueous NaHCO₃ extracted with methylene chloride. Theorganic extract was dried over MgSO₄ and concentrated. The residue waschromatographed (silica gel; methylene chloride:methanol:NH₄ OH10:1:0.1) to afford to give 282 mg (56%) of the free base of the titlecompound. The base was converted to the salt by treatment with benzoicacid in ether to give the title compound (207 mg): MS (CI/NH₃) m/z 261,278 (M+H)⁺, (M+NH₄ ⁺); ¹ H NMR (D₂ O, 300 MHz) δ 2.69 (dd, J=7.0, 8.5,2H), 4.11 (m, 1H), 4.40 (d, J=4.4, 1H), 4.63 (m, 1H), 4.95 (m, 1H) 7.53(m, 8H), 7.93 (m, 7H). Anal. Calcd for C₉ H₁₀ N₂ OBrF.2 C₆ H₅ COOH: C,54.67; H, 4.39; N, 5.54. Found: C, 54.45; H, 4.25; N, 5.58.

31b. 3-Bromo-2-(4-nitrophenylazo)-5-hydroxypyridine

5-Bromo-3-pyridinol from Example 12b (8.7 g, 0.050 mmol) and KOH (1.1 g,19.6 mmol) were dissolved in water (200 mL). A suspension ofp-nitrobenzenediazonium tetrafluoroborate (11.8 g, 0.50 mol, prepared asdescribed in J. Org. Chem., 44: 1572-15783 (1979)) was added. Thereaction was stirred for 1 hour, diluted with acetic acid (50 mL) andfiltered. The crude product was allowed to air dry, then chromatographed(silica gel; chloroform/methanol, 95:5-90:10) to provide the titlecompound (5.45 g, 34% yield): MS (CI/NH₃) m/z 323, 325 (M+H)⁺ ; NMR(DMSO-d₆, 300 MHz) δ 8.48-8.43 (m, 2H), 8.21 (d, J=2.4 Hz, 1H),8.09-8.06 (m, 2H), 7.72 (d, J=2.4 Hz, 1H).

31c. 2-Amino-3-bromo-5-hydroxypyridine

The compound from 31b above (5.0 g, 15.8 mmol) and tin chloride (25 g,111 mmol) were suspended in concentrated HCl and ethanol (150 mL), andthe mixture was heated at reflux for 1 hour. The mixture was cooled to0° C., then filtered. The filtrate was neutralized with sodiumbicarbonate (180 g) and extracted with ethyl acetate. The organicextracts were washed with brine, dried (MgSO₄) and concentrated. Theresidue was chromatographed (silica gel; chloroform/methanol/NH₄ OH,95:5:0.5-90:10:1) to afford the title compound (3.3 g, 34% yield): MS(CI/NH₃) m/z 189, 191 (M+H)⁺ ; ¹ H NMR (DMSO-d₆, 300 MHz) δ 7.57 (d,J=2.6 Hz, 1H), 7.43 (d, J=2.6 Hz, 1H).

31d. 3-Bromo-2-fluoro-5-hydroxypyridine

The compound from 31c (3.0 g, 15.9 mmol) was dissolved in HF.pyridine(50 mL). The solution was cooled to 0° C. and stirred under nitrogen,then sodium nitrite (1.09 g, 15.8 mmol) was added in portions over 20minutes. The mixture was heated to 50° C. for 1 hour, cooled to 0° C.and basified with 20% aqueous NaOH. The aqueous phase was washed withmethylene chloride (5×100 mL), neutralized with HCl, and extracted withethyl acetate (5×100 mL). The organic extracts were dried (MgSO₄),filtered and concentrated in vacuo, yielding the title compound as a tansolid: MS (CI/NH₃) m/z 192, 194 (M+H)⁺. ¹ H NMR (DMSO-d₆, 300 MHz) δ9.38 (d, J=2.6 Hz, 1H), 9.20 (d, J=2.6 Hz, ¹ H).

Example 32 5-((2S)-azetidinylmethoxy)-3-methyl-2-fluoropyridine benzoate

32a. 5-((2S)-azetidinylmethoxy)-3-methyl-2-fluoropyridine benzoate

The procedure of Example 6 was followed, substituting2-fluoro-5-hydroxy-3-methylpyridine (Example 32e below) and(S)-1-benzyloxycarbonyl-2-azetidinemethanol (Example 7c above) for3-hydroxypyridine and (R)-1-benzyloxycarbonyl-2-azetidinemethanol,respectively to afford6-fluoro-5-methyl-3-(1-benzyloxycarbonyl-(2S)-azetidinylmethoxy)pyridinein 60% yield: MS (CI/NH₃) m/z 331 (M+H)⁺ 348 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃300 MHz) δ 7.63 (br s, 1H), 7.29 (m, 5H), 7.18 (br s, 1H), 5.05 (m, 2H),4.59 (m, 1H), 4.3 (br s, 1H), 4.09 (m, 1H), 3.99 (m, 1H), 2.26-2.05 (s,3H). The benzyloxycarbonyl group of the above product was removed byhydrogenolysis (10% Pd/C, MeOH, 1 atmosphere hydrogen), and the salt wasprepared by treatment of the free amine with benzoic acid in Et₂ O togive the title compound as an off-white solid (53%): mp 104-108° C.;[α]_(D) -5.55 (c 0.55, MeOH); ¹ H NMR (DMSO) δ 7.90 (m, 2H), 7.70 (s,1H), 7.51-7.48 (m, 2H), 7.42-7.39 (t, J=7.2 Hz, 2H), 4.27 (m, 1H), 4.17(dd, J=7.3, 10.4 Hz, 1H), 4.08 (dd, J=4.9, 10.4 Hz, 1H), 3.79 (m, 1H),3.47 (m, 1H), 2.35 (m, 1H), 2.19 (s, 3H), 2.16 (m, 1H); MS (CI/NH₃): m/z197 (M+H), 214 (M+NH₄)⁺. Anal. Calcd for C₁₀ H₁₃ N₂ OF.C₇ H₆ O₂ : C,64.14; H, 6.02; N, 8.80. Found: C, 63.90; H, 6.10; N, 8.70.

32b. 2-fluoro-3-methyl-5-nitropylidine

2-Chloro-3-methyl-5-nitropyridine (15.0 g, 86.9 mmol; from MaybridgeChemical Co.), KF (12 g, 258 mmol), and tetraphenylphosphonium bromide(20 g, 47.7 mmol) were combined in 200 mL of acetonitrile and heated atreflux for 4 days. The mixture was diluted with Et₂ O (500 mL),filtered, and the solution was concentrated. The residue was trituratedwith hot hexane, then the combined hexane solutions were concentrated togive 8.4 g (60%) of the title compound: ¹ H NMR (DMSO-d₆, 300 MHz) δ8.95 (dd, J=1.6 Hz, 1H), 8.43 (m, 1H), 2.42 (s, 1H); MS (CI/NH₃) m/z:157 (M+H)⁺.

32c. 3-Amino-6-fluoro-5-methylpyridine

2-Fluoro-3-methyl-5-nitropyridine (from Step 32b above) was combinedwith 100 mg of 5% Pd/C in EtOH (100 mL), and the mixture was stirredunder an atmosphere of hydrogen for 16 hours. The mixture was filteredand concentrated. The crude product was chromatographed (silica gel;CHCl₃ /MeOH, 99:1 to 94:6) to yield 5.2 g (78%) of the title compound: ¹H NMR (DMSO-d₆, 300 MHz) δ 7.26 (t, J=2.7 Hz, 1H), 6.95 (dd, J=8.1 Hz,1H), 5.11 (br, s, 2H), 2.10 (s, 3H); MS (CI/NH₃) m/z: 127 (M+H)⁺, 144(M+NH₄)⁺.

32d. 3-acetoxy-6-fluoro-5-methylpyridine

To boron trifluoride etherate (10 mL, 81 mmol) at -15° C. under N₂ wasadded the product of step 32c (5.1 g, 40 mmol) in DME (30 mL).tert-Butyl nitrite (5.5 mL, 46 mmol, Aldrich) was added at a such a ratethat the temperature remained below 0° C. Additional DME (25 mL) wasthen added. After 10 minutes at -10° C. the reaction was warmed to 5° C.and stirred for 30 minutes. Pentane (400 mL) was then added to thereaction mixture, the solid was collected by suction filtration, washedwith cold ether, air dried, and dissolved in 100 mL acetic anhydride.The resulting solution was heated to 77±5° C. for 1 hour. The solventwas removed in vacuo, and the residue was suspended in saturated aqueousNa₂ CO₃ (200 mL) and extracted with ethyl ether. The ether solution wasdried (MgSO₄) and concentrated . The crude product was chromatographed(silica gel; hexane/EtOAc 9:1 to 7:3) to yield 3.62 g (53%) of the titlecompound: MS m/z: 170 (M+H)⁺, 187 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃ 300 MHz) δ7.8 (m, 1H) 7.34 (m, 1H), 2.32 (s, 3H), 2.29 (s, 3H).

32e. 2-Fluoro-5-hydroxy-3-methylpyridine

The product of step 32d (3.6 g, 21.3 mmol) was dissolved in 20% aqueousNaOH (25 mL). After complete consumption of the starting material thesolution was neutralized by addition of HCl. The aqueous mixture wasextracted with ethyl acetate. The organic extracts were dried (MgSO4),and the solvent was evaporated. The crude product was triturated withhexane to yield 2.35 g (87%) of the title compound: MS (CI/NH₃) m/z: 128(M+H)⁺, 145 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃, 300 MHz) δ: 7.61(t, J=2.2 Hz,1H), 7.17 (m, 1 H), 2.25 (s, 3H).

Example 33 5-((2S)-azetidinylmethoxy)-3-chloro-2-fluoropyridine tosylate

33a. 5-((2S)-azetidinylmethoxy)-3-chloro-2-fluoropyridine tosylate

Following the procedures of Example 10, replacing3-fluoro-5-hydroxypyridine thereof with3-chloro-2-fluoro-5-hydroxypyridine (3.0 mmol),5-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)-3-chloro-2-fluoropyridinewas prepared (668 mg, 70%) as a colorless oil: [α]_(D) -56.6 (c 2.7, CH₂Cl₂); ¹ H NMR (CDCl₃) δ 1.43 (s, 9H), 2.24-2.40 (m, 2H), 3.84-3.91 (m,2H), 4.12 (dd, J=2.7, 11.2 Hz, 1H); 4.36 (m, 1H); 4.50 (m, ¹ H), 7.46(dd, J=3.1, 7.5 Hz, 1H), 7.78 (dd, J=2.0, 2.7 Hz, 1H); MS (CI/NH₃) m/z:317, 319 (M+H)⁺. A solution of the above compound (780 mg, 2.46 mmol)was stirred in a 1:1 solution of CH₂ Cl₂ /TFA at 0° C. After 30 minutesthe reaction solution was concentrated, and the residue was diluted withCH₂ Cl₂ and washed with saturated K₂ CO₃. The organic extract was dried(Na₂ SO₄) and concentrated. Chromatography (silica gel, 90:10:1 CH₂ Cl₂/MeOH/NH₄ OH) afforded 407 mg (76%) of the free base of the titlecompound: MS (CI/NH₃) m/z: 217, 219 (M+H)⁺. The free amine (387 mg, 1.79mmol) was dissolved in MeOH (5 mL) and p-toluenesulfonic acidmonohydrate (340 mg, 1.79 mmol) was added. The solution was concentratedand the solid was recrystallized from MeOH/hexane to afford the titlecompound as a white solid: mp 99° C.; ¹ H NMR (D₂ O) δ 2.40 (s 3H), 2.69(q, J=8.5 Hz, 2H), 4.05-4.18 (m, 2H), 4.41 (d, J=4.3 H), 4.94 (m, 1H),7.37 (d, J=8.0 Hz, 2H), 7.69 (d, J=8.0 Hz, 2H), 7.82 (dd, J=3.1, 7.31Hz, 1H), 7.87 (m, 1H); MS (CI/NH₃): m/z 217, 219 (M +H)⁺, 234, 236(M+NH₄)⁺ ; Anal. Calcd for C₉ H₁₀ N₂ OFCl.C₇ H₈ O₃ S: C, 49.42; H, 4.67;N, 7.20. Found: C, 49.14; H, 4.56; N, 6.98.

33b. 3-Chloro-2-(4-nitrophenylazo)-5-hydroxypyridine

To a solution of 5-chloro-3-pyridinol (20.0 g, 0.154 mol, Aldrich) andKOH (13.0 g, 0.232 mol) in 300 mL of water at 0° C. was addedp-nitrobenzenediazonium tetrafluoroborate (36.6 g, 0.154 mol, Aldrich).After 1 hour, 50 mL of glacial acetic acid was added, and the bright redprecipitate was filtered and air-dried. Chromatography (silica gel; CH₂Cl₂ /MeOH, 95:5-90:10) afforded the title compound as a bright red solid(28.8 g, 67%): ¹ H NMR (DMSO-d₆, 300 MHz) δ 7.14 (d, J=2.4 Hz, 1H), 7.89(d, J=2.4 Hz, 1H), 8.00 (m, 2H), 8.39 (m, 2H); MS (CI/NH₃) m/z: 279, 281(M+H)⁺.

33c. 2-Amino-3-Chloro-5-hydroxypyridine

To a suspension of the diazo compound from Step 33b (8.82 g, 31.7 mmol)and copper(I) chloride (9.40 g, 95.0 mmol Aldrich) in MeOH (150 mL) at0° C. was added potassium borohydride portion wise (12.0 g, 221 mmol,nitrogen evolution). The dark mixture was allowed to warm to ambienttemperature, stirred for 1 hour, then filtered and concentrated. Theresidue was dissolved in glacial acetic acid (75 mL) and 30% HBr/HOACwas added (75 mL). The mixture was filtered (HOAc wash), and thefiltrate was concentrated to provide 8.64 g (89%) of the unpurifiedtitle compound as the dihydrobromide salt: ¹ H NMR (DMSO-d₆, 300 MHz) δ5.40 (br s, 1H), 7.16 (d, J=2.6 Hz, 1H), 7.56 (d, J=2.2 Hz, 1H), 8.25(br s, 2H); MS (CI/NH₃) m/z: 145, 147 (M+H)⁺.

33d. 3-chloro-2-fluoro-5-hydroxypyridine

To a 0° C. solution of compound from Step 33c (11.8 g, 38.4 mmol)dissolved in HF-pyridine (100 g, Aldrich) was added sodium nitrite (2.92g, 42.3 mmol) in portions. The reaction mixture was warmed to 50° C. for1 hour, then cooled to 0° C. and basified with 20% aqueous NaOH. Theaqueous phase was washed with EtOAc, neutralized with 1 N aqueous HCl,and extracted with ethyl acetate. The latter extracts were dried(MgSO₄), filtered and concentrated in vacuo. Purification bychromatography (silica gel; hexane/EtOAc, 50:50) afforded 1.49 g (25%)of the title compound as a tan solid: ¹ H NMR (DMSO-d₆, 300 MHz) δ 7.54(m, 1H), 7.67 (m, 1H); 10.44 (s, 1H); MS (CI/NH₃) m/z 148, 150 (M+H)⁺.

Example 34 5-Bromo-6-methyl-3-((2S)-azetidinylmethoxy)pyridinedihydrochloride

34a. 5-Bromo-6-methyl-3-((2S)-azetidinylmethoxy)pyridine dihydrochloride

Triphenylphosphine (6.3 g, 24 mmol) was dissolved in THF (100 mL),cooled to 0° C. and treated with DEAD (3.8 mL, 24 mmol) for 15 minutes.Then the 5-bromo-6-methyl-3-pyridinol (3 g, 16 mmol, see Step 34e below)and 1-t-butyloxycarbonyl-(2S)-azetidinemethanol (3.4 g, 18 mmol, fromStep 7c) were added, and the mixture was allowed to warm slowly toambient temperature. After 3 days, the solvent was evaporated, and theresidue was chromatographed (silica gel; hexanes/EtOAc, 4:1) to providethe title compound as an oil, contaminated with hydrazine byproductderived from the DEAD: MS (CI/NH₃) m/z: 357 (M+H)⁺, 279. The productfrom above (0.40 g, 1.12 mmol) was dissolved in methylene chloride (4mL) and treated with TFA (2 mL) at 0° C. for 1 hour. The solution wasconcentrated, and the residue was diluted with saturated aqueousbicarbonate and extracted with methylene chloride. The organic extractwas washed with H₂ O, and dried (MgSO₄). Evaporation of the solventprovided 0.25 g (76%) of neutral product, which was dissolved in etherand treated with 1 N HCl in ether. The resulting solid was collected andwashed with fresh ether to provide 151 mg (41%) of the title compound:mp 153-155° C.; [α]_(D) -7.4 (c 0.54, MeOH); ¹ H NMR (CD₃ OD) δ2.63-2.76 (m, 2H), 2.78 (s, 3H), 4.04-4.18 (m, 2H), 4.50-4.63 (m, 2H),4.88-4.96 (m, 1H), 8.50 (d, J=2 Hz, 1H), 8.10 (d, J=2 Hz, 1H); MS(CI/NH3): m/z 257 (M+H)⁺, 274 (M+NH₄)⁺ ; Anal. Calcd for C₁₀ H₁₃ N₂ OBr.2 HCl: C, 36.39; H, 4.58; N, 8.49. Found: C, 36.31; H, 4.66; N, 8.41.

34b. 3-bromo-2-methyl-5-nitropyridine

A solution of diethyl malonate (17.6 mL, 0.116 mol) in diethyl ether(250 mL) at ambient temperature was treated with sodium hydride (80% inmineral oil, 3.5 g, 0.116 mol), and the mixture was stirred for 1 hour.Then 3-bromo-2-chloro-5-nitropyridine (25 g, 105 mmol; prepared from2-hydroxy-5-nitropyridine according to the procedure of V. Koch and S.Schnatterer, Synthesis 1990, 499-501) was added in portions over 5minutes. After the mixture had stirred for 1 hour, the solvent wasevaporated, and the residue was heated at 100° C. for 1 hour. After themixture had cooled, 12 N H₂ SO₄ was added, and the mixture was heated atreflux for about 16 hours. The mixture was allowed to cool to ambienttemperature, then further cooled as it was treated with 50% NaOH to givean alkaline pH. The resulting solution was extracted with CHCl₃ (3×),and the organic extracts were washed with H₂ O, dried (MgSO₄) andevaporated to afford 17.1 g of the title compound as a red oil: ¹ H NMR(CDCl₃, 300 MHz) δ 2.81 (s, 3H), 8.61 (d, J=2 Hz, 1H), 9.26 (d, J=2 Hz,1H).

34c. 5-amino-3-bromo-2-methylpyridine

The compound of Example 34b above (17.1 g, 78.8 mmol) was dissolved inHOAc (50 mL) and water (150 mL) and treated with iron powder (13.3 g,236 mmol) added in portions over 2 hours. The mixture was filtered, andthe filter cake was washed with EtOAc. The layers were separated, andthe aqueous phase was extracted with EtOAc. The combined organicfractions were washed with 1 M sodium bicarbonate and water, then dried(MgSO₄) and concentrated to afford 12.65 g (86%) of the title compound:MS (CI/NH₃) m/z: 187 (M+H)⁺, 204 (M+NH₄)⁺.

34d. 5-Acetoxy-3-bromo-2-methylpyridine

The compound of Example 34c (12.6 g, 67 mmol) was treated with t-butylnitrite and BF₃.OEt₂ followed by acetic anhydride according to theprocedure of Example 1f. The crude product was chromatographed (silicagel; hexanes/EtOAc, 4:1) to afford the title compound (12.0 g, 58%): MS(CI/NH₃) m/z: 230 (M+H)⁺.

34e. 3-bromo-5-hydroxy-2-methylpyridine

The product of Example 34d was stirred with 15% aqueous NaOH (75 mL) at0° C., and the mixture was allowed to warm to ambient temperature. After1 hour, the mixture was acidified with 6 N aqueous HCl with cooling, andthe resulting suspension was extracted with EtOAc. The EtOAc was washedwith H₂ O, dried (MgSO₄) and concentrated to provide 7.0 g (95%) of thetitle compound: ¹ H NMR (CDCl₃, 300 MHz) δ 2.59 (s, 3H), 7.46 (d, J=2Hz, 1H), 8.10 (d, J=2Hz, 1H); MS (CI/NH₃) m/z: 188 (M+H)⁺, 207 (M+NH₄)⁺.

Example 35 6-Methyl-5-vinyl-3-((2S)-azetidinylmethoxy)pyridinehydrochloride

5-Bromo-6-methyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine(0.95 g, 2.7 mmol, Step 34a above) was treated with vinyl tributyltin(1.62 mL, 5.56 mmol) and tetrakis(triphenylphosphino)palladium(0) (0.29g, 0.25 mmol) in toluene (30 mL) at 90° C. overnight. The reaction wascooled to ambient temperature and chromatographed on silica gel with 2:1hexane-EtOAc eluent to provide6-methyl-5-vinyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine(0.49 g, 60%): MS (CI/NH₃) m/z: 305 (M+H)⁺ ; ¹ H NMR (300 MHz, CDCl₃) δ1.42 (s, 9H), 2.22-2.38 (m, 2H), 2.52 (s, 3H), 3.91 (dt, J=2, 6 Hz, 2H),4.13 (dd, J=3, 10 Hz, 1H), 4.30-4.36 (m, 1H), 4.49-4.55 (m, 1H), 5.40(dd, J=1, 11 Hz, 1H), 5.64 (dd, J=1, 17 Hz, 1H), 6.84 (dd, J=11, 17 Hz,1H), 7.32 (d, J=3 Hz, 1H), 8.13 (d, J=3 Hz, 1H). The product from above(0.47 g,1.53 mmol) was treated with 8 mL of 1:1 TFA-methylene chlorideat 0° C. for 2 hours. The volatile components were evaporated in vacuo,and the residue was diluted with saturated aqueous sodium bicarbonateand extracted with CH₂ Cl₂. The combined organic layers were washed withwater and dried over MgSO₄ to provide the product (277 mg, 89% yield).Half of the sample was dissolved in ether and treated with 1 M HCl inether to provide 85 mg of the title compound as an off-white solid: mp154-155° C.; [α]_(D) -8.9 (c 0.45, MeOH); ¹ H NMR (CD₃ OD) δ 2.63-2.77(m, 2H), 2.74 (s, 3H), 4.08-4.16 (m, 2H), 4.52-4.64 (m, 2H), 4.85-4.95(m, 1H), 5.80 (d, J=11 Hz, 1H), 6.15 (d, J=17 Hz, 1H), 7.02 (dd, J=11,17 Hz, 1H), 8.36 (d, J=2 Hz), 1H, 8.48 (d, J=2 Hz, 1H); MS (CI/NH₃) m/z;205 (M+H)⁺ ; Anal. Calcd for C₁₂ H₁₆ N₂ O.2.1 HCl: C, 51.32; H, 6.50; N,9.97. Found: C, 51.60; H, 6.21; N, 9.82.

Example 36 6-Ethyl-6-methyl-3-((2S)-azetidinylmethoxy)pyridinehydrochloride

6-Methyl-5-vinyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine(0.26 g, 0.86 mmol, from Example 35 above) was dissolved in MeOH (15 mL)and treated with 10% Pd/C (50 mg) and 1 atm hydrogen gas. After 1 day,the catalyst was removed, the solvent evaporated, and the residue waschromatographed (silica gel; hexanes-EtOAc, 1:1) to provide5-ethyl-6-methyl-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine(0.12 g, 45%): MS (CI/NH₃) m/z: 307 (M+H)⁺ ; ¹ H NMR (300 MHz, CDCl₃) δ1.23 (t, J=7 Hz, 3H), 1.42 (s, 9H), 2.23-2.38 (m, 2H), 2.47 (s, 3H),2.60 (q, J=7 Hz, 2H), 3.86-3.93 (m, 2H), 4.12 (dd, J=3, 9 Hz, 1H), 4.29(dd, J=5,10 Hz, 1H), 4.43-4.53 (m, 1H), 7.04 (d, J=3 Hz, 1H), 8.05 (d,J=3 Hz, 1H). The product from above (0.26 g, 0.85 mmol) was treated with10 mL of 1:1 TFA-methylene chloride at 0° C. for 1 hour. The residue wasdiluted with saturated sodium bicarbonate and extracted into CHCl₃. Theorganic layer was washed with water, dried over MgSO₄, and evaporated toprovide of the free base of the title compound (132 mg, 75%). This wasdissolved in ether and treated with 1 M HCl in ether and the resultingsalt collected by filtration to provide the title compound (52 mg, 25%).The mother liquor was evaporated to further provide 73 mg of the titlecompound: mp 150-153° C.; [α]_(D) -7.6 (c 0.62, MeOH); ¹ H NMR (300 MHz,CD₃ OD) δ 1.34 (t, J=7 Hz, 3H), 2.63-2.76 (m, 2H), 2.72 (s, 3H),4.04-4.19 (m, 2H), 4.49-4.63 (m, 2H), 4.88-4.97 (m, ¹ H), 8.14 (d, J=2Hz, 1H), 8.40 (d, J=2 Hz); MS (CI/NH₃): m/z 207 (M+H⁺). Anal. Calcd forC₁₂ H₁₈ N₂ O.2HCl.0.1 H₂ O: C, 51.29; H, 7.25; N, 9.97. Found: C, 51.21;H, 7.14; N, 9.77.

Examples 37-53

R-enantiomers of Formula I, with X and Y defined as shown in Table 5,are prepared, each according to the procedure used for preparation ofthe corresponding (S)-enantiomer as presented in Table 5, and using thecorresponding N-protected (R)-2-azetidinemethanol as a starting materialin place of the N-protected (S)-2-azetidinemethanol.

    ______________________________________                                                                  Using procedure of                                    Ex. X Y Example:                                                            ______________________________________                                        37       Me       H       20                                                    38 H Cl 21                                                                    39 H Br 12                                                                    40 H Et 23                                                                    41 H n-Pr 24                                                                  42 H vinyl 22                                                                 43 Cl Me 25                                                                   44 Cl Et 27                                                                   45 Cl n-Pr 28                                                                 46 Cl n-Bu 29                                                                 47 Cl vinyl 26                                                                48 Cl ethynyl 30                                                              49 F Br 31                                                                    50 F Me 32                                                                    51 Me Br 34                                                                   52 Me Et 36                                                                   53 Me vinyl 35                                                              ______________________________________                                    

Example 54 1-(N-BOC-L-Alanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

To a solution of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (fromExample 8, 102 mg, 060 mmol) in THF (20 mL) was added N-BOC-L-alanine(106 mg, 1.0 eq), 1-(dimethylaminopropyl)-3-ethylcarbodiimide HCl (107mg, 1.0 eq), and 4-(dimethylamino)pyridine (68 mg, 1.0 eq), and theresulting mixture was stirred at 20-25° C. for approximately 2 hours.The volatiles were removed under vacuum, and the residue purified bychromatography on silica gel, eluting with 10%MeOH/CH₂ Cl₂. The productwas obtained as a yellow oil (155 mg, 73%): ¹ H NMR (300 MHz, CDCl₃) δ7.85 (m, 1H), 7.37 (ddd, J=3, 7, 10 Hz, 1H), 6.84 (dd, J=3, 9 Hz, 1H),5.0-5.2 (m, 1H), 4.0-4.7 (br m, 5H), 3.49 (d, J=6 Hz, 1H), 2.47 (m, 2H),1.41 (s, 9H), 1.29 (d, J=7 Hz, 3H); MS (CI/NH₃) m/e 354, 298, 254;[α]_(D) ²⁰ -49.78° (c=0.10, CH₂ Cl₂); Analysis calc'd for C₁₇ H₂₄ N₃ O₄F. 0.55 H₂ O: C, 56.20; H, 6.96; N, 11.57; found: C, 56.23; H, 7.03; N,11.26.

Example 55 1-(N-acetyl-L-phenylalanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof withN-acetyl-L-phenylalanine. The product was obtained as a colorless oil in56% yield: ¹ H NMR (300 MHz, CDCl₃) δ 7.81 (m, 1H), 7.1-7.4 (m, 6H),6.84 (m, 1H), 6.12 (m, 1H), 4.4-5.0 (m, 2H), 3.5-4.2 (m, 3H), 2.97 (m,3H), 2.0-2.2 (m, 2H), 1.96 (s, 3H); MS (CI/NH₃) m/e 372; [α]_(D) ²⁰-46.21° (c=0.20, CH₂ Cl₂); Analysis calc'd for C₂₀ H₂₂ N₃ O₃ F: C,64.68; H, 5.97; N, 11.31; found: C, 64.44; H, 5.99; N, 11.06.

Example 56 1-(N-acetyl-L-alanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof withN-acetyl-L-alanine. The product was obtained as a colorless oil in 78%yield: ¹ H NMR (300 MHz, CDCl₃) δ 7.85 (m, 1H), 7.37 (m, 1H), 6.86. m(1), 6.2 (m, 1H), 4.4-4.8 (m, 3H), 3.9-4.4 (m, 3H), 2.48 (m, 2H), 1.96(s, 3H), 1.30 (d, J=7 Hz, 3H); MS (CI/NH₃) m/e 296, 183; [α]_(D) ²⁰-86.72° (c=0.15, CH₂ Cl₂); Analysis calc'd for C₁₄ H₁₈ N₃ O₃ F.0.4 H₂ O:C, 56.58; H, 6.26; N, 13.89; found: C, 55.66; H, 6.38; N, 13.93.

Example 57 1-(N-BOC-L-phenylalanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof withN-BOC-L-phenylalanine. The product was obtained as a pale oil in 98%yield: ¹ H NMR (300 MHz, CDCl₃) δ 7.83 (m, 1H), 7.30 (m, 5H), 7.15 (m,1H), 6.83 (dd, J=3, 5 Hz, 1H), 5.18 (m, 1H), 4.46 (m, 2H), 4.25 (m, 1H),3.6-4.2 (m, 2H), 2.96 (m, 3H), 2.13 (m, 2H), 1.41 (s, 9H); MS (CI/NH₃)m/e 430, 330; [α]_(D) ²⁰ 36.72° (c=0.15, CH₂ Cl₂); Analysis calc'd forC₂₃ H₂₈ N₃ O₄ F.0.1 H₂ O: C, 64.05; H, 6.59; N, 9.74; found: C, 64.03;H, 6.28; N, 9.73.

Example 58 1-(monomethyl phthalyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof with monomethylphthalate. The product was obtained as a colorless oil in 99% yield: ¹ HNMR (300 MHz, CDCl₃) δ 7.96 (m, 2H), 7.52 (m, 3H), 7.22 (m, 1H), 6.87(m, 1H), 4.1-4.9 (m, 3H), 3.91 (s, 3H), 3.78 (m, 2H), 2.44 (m, 2H); MS(DCI/NH₃) m/e 345; [α]_(D) ²⁰ -18.21° (c=0.20, CH₂ Cl₂); Analysis C₁₈H₁₇ N₂ O₄ F.0.55 H₂ O: C, 61.03; H, 5.15; N, 7.91; found: C, 61.09; H,5.12 N, 7.90.

Example 59 1-(N-Acetyl-D-phenylalanlyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof withN-acetyl-D-phenylalanine. The product was obtained as a white foam in97% yield: ¹ H NMR (300 MHz, CDCl₃) δ 7.82 (m, 1H), 7.2-7.5 (m, 6H),6.87 (m, 1H), 6.27 (m, 1H), 4.6-5.0 (m, 2H), 3.8-4.2 (m, 3H), 3.54 (m,1H), 2.9-3.1 (m, 2H), 2.01 (s, 3H), 1.8-2.4 (m, 2H); MS (DCI/NH₃) m/e372; [α]_(D) ²⁰ +56.67° (c=0.15, CH₂ Cl₂); Analysis calc'd for C₂₀ H₂₂N₃ O₃ F.0.45 H₂ O: C, 63.30; H, 6.08; N, 11.07; found: C, 63.29; H,5.93; N, 11.09.

Example 60 1-(N-Acetyl-D-alanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof withN-acetyl-D-alanine. The product was obtained as a pale yellow oil in 86%yield: ¹ H NMR (300 MHz, CDCl₃) δ 7.86 (m, 1H), 7.36 (m, 1H), 6.85 (m,1H), 6.26 (m, 1H), 4.71 (m, 1H), 4.1-4.6 (m, 5H), 2.47 (m, 2H), 1.98 (s,3H), 1.22 (d, J=7 Hz, 3H); MS (DCI/NH₃) m/e 296; [α]_(D) ²⁰ +95.67°(c=0.30, CH₂ Cl₂); Analysis calc'd for C₁₄ H₁₈ N₃ O₃ F.0.40 H₂ O: C,55.58; H, 6.26; N, 13.89; found: C, 55.57; H, 6.30; N, 13.80.

Example 61 1-(4(Diethylaminomethyl)benzoyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof with4(dimethylaminomethyl)benzoic acid. The product was obtained as a paleyellow oil in 59% yield: ¹ H NMR (300 MHz, CDCl₃) δ 7.90 (m, 1H), 7.54(m, 2H), 7.38 (m, 4H), 6.83 (m, 1H), 4.88 (m, 1H), 4.1-4.6 (m, 3H), 3.60(br s, 2H), 2.50 (m, 6H), 1.03 (d, J=7 Hz, 6H); MS (DCI/NH₃) m/e 372;[α]_(D) ²⁰ +97.00° (c=0.60, CH₂ Cl₂); Analysis calc'd for C₂₁ H₂₆ N₃ O₂F.0.3 H₂ O: C, 66.93; H, 7.11; N, 11.15; found: C, 66.99; H, 7.13; N,11.17.

Example 62 1-(N-BOC-D-phenylalanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof withN-BOC-D-phenylalanine. The product was obtained as a colorless oil in79% yield: ¹ H NMR (300 MHz, CDCl₃) δ 7.82 (m, 1H), 7.31 (m 3), 7.19 (m,3H), 6.87 (m, 1H), 5.25 (m, 1H), 4.62 (m, 1H), 3.7-4.4 (m, 4H), 3.53 (m,1H), 2.95 (m, 2H), 1.8-2.4 (m, 2H), 1.37 & 1.44 (s, 9H); MS (DCI/NH₃)m/e 430, 274, 330; [α]_(D) ²⁰ +33.20° (c=0.20, CH₂ Cl₂); Analysis calc'dfor C₂₃ H₂₈ N₃ O₄ F.0.65 H₂ O: C, 62.61; H, 6.69; N, 9.52; found: C,62.64; H, 6.66; N, 9.36.

Example 63 1-(N-BOC-D-alanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof with N-BOC-D-alanine.The product was obtained as a colorless oil in 99% yield: ¹ H NMR (300MHz, CDCl₃) δ 7.87 (m, 1H), 7.36 (ddd, J=3, 6, 9 Hz, 1H), 6.85 (dd, J=3,9 Hz, 1H), 5.20 (m, 1H), 4.72 (m, 1H), 4.53 (m, 1H), 4.1-4.3 (m, 4H),2.46 (m, 2H), 1.43 (s, 9H), 1.20 (d, J=7 Hz, 3H); MS (DCI/NH₃) m/e 354,298, 254; [α]_(D) ²⁰ +79.20° (c=0.52, CH₂ Cl₂); Analysis calc'd for C₁₇H₂₄ N₃ O₄ F. 0.25 H₂ O: C, 57.05; H, 6.90; N, 11.74; found: C, 57.09; H,6.91; N, 11.58.

Example 64 1-(2-oxo-tetrahydrofuran-4-(S)-carboxoyl) prodrug of5-(2R)-azetidinylymethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof withS-4-carboxybutyrolactone. The product was obtained as a colorless oil in65% yield: ¹ H NMR (300 MHz, CDCl₃) δ 7.86 (m, 1H), 7.37 (m, 1H), 6.86(m, 1H), 4.7-5.1 (m, 2H), 4.0-4.6 (m, 4H), 2.43 (m 6); MS (CI/NH₃) m/e295, 199, 174, 123; [α]_(D) ²⁰ +94.0° (c=0.30, CH₂ Cl₂); Analysis calc'dfor C₁₄ H₁₅ N₂ O₄ F. 0.4 H₂ O: C, 55.77; H, 5.28; N, 9.24; found: C,55.88; H, 5.39; N, 9.28.

Example 65 1-(2-oxo-tetrahydrofuran-4-(R)-carboxoyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof withR-4-carboxybutyrolactone. The product was obtained as a pale yellow oilin 63% yield: ¹ H NMR (300 MHz, CDCl₃) δ 7.88 (m, 1H), 7.37 (m, 1H),6.86 (m, 1H), 4.86 (m, 1H), 4.76 (m, 1H), 4.60 (m, 1H), 4.32 (t, J=8 Hz,2H), 4.11 (m, 1H), 2.50 (m, 6H); MS (DCI/NH₃) m/e 295; [α]_(D) ²⁰+77.50° (c=0.16, CH₂ Cl₂); Analysis calc'd for C₁₄ H₁₅ N₂ O₄ F.0.4 H₂ O:C, 55.77; H, 5.28; N, 9.29; found: C, 55.82; H, 5.34; N, 9.21.

Example 66 1-(2-(hydroxymethyl)benzoyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared according to the procedure of Example54, except replacing the N-BOC-L-alanine thereof with2-hydroxymethylbenzoic acid. The product was obtained as a pale oil in44% yield: ¹ H NMR (300 MHz, CDCl₃) δ 7.94 (m 1), 7.37 (m, 5H), 6.87 (m,1H), 4.90 (m, 1H), 4.71 (m, 1H), 4.60 (br d, J=11 Hz, 1H), 4.43 (br d,J=11 Hz, 1H), 4.18 (m, 2H), 3.99 (m 1), 2.50 (m, 2H); MS (DCI/NH₃) m/e317, 200, 183, 169, 152; [α]_(D) ²⁰ -12.18° (c=0.12, CH₂ Cl₂); Analysiscalc'd for C₁₇ H₁₇ N₂ O₃ F.0.1 H₂ O: C, 64.18; H, 5.45; N, 8.81; found:C, 64.24; H, 5.39; N, 8.73.

Example 67 1-(L-phenylalanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

BF₃.Et₂ O (103 mg, 1.0 eq) was added to a solution of the1-(N-BOC-L-phenylalanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example 57, 310 mg,0.70 mmol) in methylene chloride (20 mL). The reaction was stirred atroom temperature for 1 h, then quenched with 5% NaHCO₃ and extractedinto methylene chloride (100 mL), and dried over MgSO₄. The solvent wasremoved under vacuum, and the residue purified by chromatography onsilica gel, eluting with 10% MeOH/CH₂ Cl₂. The product was obtained as acolorless oil in 53% yield: ¹ H NMR (300 MHz, CDCl₃) δ 7.84 (m, 1H),7.26 (m, 6H), 6.84 (dd, J=3, 9 Hz, 1H), 4.53 (m, 1H), 4.46 (dd, J=5, 10Hz, 1H), 4.16 (dd, J=3, 10 Hz, 1H), 3.93 (q, J=8 Hz, 1H), 3.42 (m, 1H),3.14 (m, 1H), 2.91 (dd, J=8, 13 Hz, 1H), 2.82 (dd, J=7, 13 Hz, 1H), 2.23(m, 1H), 2.09 (m, 1H); MS (DCI/NH₃) m/e 330, 120; [α]_(D) ²⁰ -52.71°(c=0.30, CH₂ Cl₂); Analysis calc'd for C₁₈ H₂₀ O₂ F. 0.5 H₂ O: C, 63.86;H, 6.26; N, 12.42; found: C, 63.77; H, 6.08; N, 12.40.

Example 68 1(L-alanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

This compound was obtained by deprotection of I-(N-BOC-L-alanyl) prodrugof 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from example 54)according to the procedure described in Example 67. The product wasobtained as a colorless oil in 26% yield: ¹ H NMR (300 MHz, CDCl₃) δ7.87 (m, 1H), 7.37 (m, 1H), 6.96 (dd, J=3, 9 Hz, 1H), 4.69 (m, 1H), 4.55(m, 1H), 4.20 (m, 2H), 4.06 (m, 1H), 3.38 (q, J=7 Hz, 1H), 2.47 (m, 2H),1.23 (d, J=7 Hz, 3H); MS (DCI/NH₃) m/e 254; [α]_(D) ²⁰ -31.62° (c=0.05,CH₂ Cl₂); Analysis calc'd for C₁₂ H₁₆ N₃ O₂ F.1.15 H₂ O: C, 52.60; H,6.73; N, 15.34; found: C, 52.58; H, 6.56; N, 15.27.

Example 69 1-(D-phenylalanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

This compound was obtained by deprotection of 1-(N-BOC-D-phenylalanyl)prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from example 62)according to the procedure described in Example 67. The product wasobtained as a colorless oil in 53% yield: ¹ H NMR (300 MHz, CDCl₃) δ7.84 (m, 1H), 7.35 (m, 1H), 7.22 (m, 5H), 6.87 (m, 1H), 4.67 (m, 1H),4.31 (m, 1H), 4.10 (m, 2H), 3.6-4.0 (m, 2H), 2.88 (m, 2H), 2.40 (m, 1H),2.24 (m, 1H); MS (DCI? NH₃) m/e 330; [α]_(D) ²⁰ +20.75° (c=0.27, CH₂Cl₂); Analysis calc'd for C₁₈ H₂₀ N₃ O₂ F.0.5 H₂ O: C, 63.89; H, 6.26;N, 12.42; found: C, 63.92; H, 6.06; N, 12.48.

Example 70 1-(D-alanyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

This compound was obtained by deprotection of the 1-(N-BOC-D-alanyl)prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from example 63)according to the procedure described in Example 67. The product wasobtained as a colorless oil, which was treated with 1 eq ofp-toluenesulfonic acid in ethanol to form the tosylate salt as acolorless semisolid (17%): ¹ H NMR (300 MHz, CD₃ OD) δ 7.90. m (1), 7.70(d, J=8 Hz, 2H), 7.59 (m, 1H), 7.23 (d, J=8 Hz, 2H), 7.00 (dd, J=3, 9Hz, 1H), 4.76 (m, 1H), 4.55 (m, 1H). 4.39 (m, 1H), 4.21 (m, 2H), 4.02(m, 1H), 2.52 (m, 2H), 2.37 (s, 3H), 1.34 (d, J=7 Hz, 3H); MS (DCI/NH₃)m/e 254, 183, 141; [α]_(D) ²⁰ +11.10° (c=0.05, EtOH); Analysis calc'dfor C₁₂ H₁₆ N₃ O₂ F.C₇ H₈ O₃ S: C, 52.42; H, 5.75; N, 7.64; found: C,53.31; H, 5.77; N, 7.34.

Example 71 1-(N-succinimidylmethyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

5-(2R)-Azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8, 150mg, 0.42 mmol) was combined with succinimide (47 mg, 1.1 eq) and K₂ CO₃(88 mg, 1.5 eq). Ethanol (20 mL) was added, followed by aqueous formalin(36%, 110 mg, 3.2 eq). The mixture was stirred at 40-45° C. for 2-3hours, then cooled to 25° C. and concentrated to a white solid. This waspurified on silica gel with 1% MeOH/EtOAc to provide the title compoundas a colorless oil (70 mg, 59%): ¹ H NMR (300 MHz, CDCl₃) δ 7.86 (m,1H), 7.41 (ddd, J=3, 6, 9 Hz, 1H), 6.85 (dd, J=3, 9 Hz, 1H), 4.34 (ABquartet, J=13 Hz, 2H), 4.02 (m, 2H), 3.76 (m, 1H), 3.43 (dt, J=3, 8 Hz,1H), 3.24 (m, 1H), 2.76 (s, 4H), 2.11 (m, 1H), 2.02 (m, 1H); MS(DCI/NH₃) m/e 294 ((M+1)), 183; Analysis calc'd for C₁₄ H₁₆ N₃ O₃ F.0.5H₂ O: C, 55.62; H, 5.67; N, 13.90; found: C, 55.76; H, 5.61; N, 13.92.

Example 72 1-(N-phthalimidylmethyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

5-(2R)-Azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) wascombined with phthalimide by the procedure described in Example 71 togive the title compound: m.p. 97-100°; ¹ H NMR (300 MHz, CDCl₃) δ 7.88(m, 2H), 7.76 (m, 3H), 7.33 (ddd, J=3, 6, 9 Hz, 1H), 6.82 (dd, J=3, 9Hz, 1H), 4.54 (s, 2H), 4.05 (m, 2H), 3.82 (m, 1H), 3.45 (m, 1H), 3.28(q, J=8 Hz, 1H), 2.13 (m, 1H), 2.00 (m, 1H); MS (DCI/NH₃) m/e 342 (M+1),183; Analysis calc'd for C₁₈ H₁₆ N₃ O₃ F.0.50 H₂ O: C, 61.70; H, 4.89;N, 11.99; found: C, 61.68; H, 4.93; N, 11.87.

Example 73 1-(N-(2-hydroxybenzoyl)aminomethyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

5-(2R)-Azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) wascombined with salicylamide by the procedure described in Example 71 togive the title compound: ¹ H NMR (300 MHz, CDCl₃) δ 7.80 (dd, J=2, 3 Hz,1H), 7.40 (t, J=8 Hz, 1H), 7.28 (m, 2H), 6.99 (d, J=8 Hz, 1H), 6.78 (m,3H), 4.39 (dd, J=6, 12 Hz, 1H), 4.24 (dd, J=5, 12 Hz, 1H), 4.05 (m, 2H),3.80 (m, 1H), 3.45 (q, J=6 Hz, 1H), 3.27 (q, J=8 Hz, 1H), 2.12 (m, 2H);MS (DCI/NH₃) m/e 332 ((M+1)), 183, 155, 138; Analysis calc'd for C₁₇ H₁₈N₃ O₃ F.0.50 H₂ O: C, 59.99; H, 5.62; N, 12.34; found: C, 59.78; H,5.67; N, 12.06.

Example 74 1-(2,5-dihydro-2-oxo-furan-4-yl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

A mixture of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (fromExample 8, 200 mg, 0.56 mmol), tetronic acid (84 mg, 1.5 eq), potassiumcarbonate (77 mg, 1 eq), and absolute ethanol (2 mL) was heated in asealed tube at 45-50° C. for 2-3 hours. The mixture was filtered, andthe filtrate was concentrated under vacuum. The product was purified bychromatography on silica gel, eluting with 2% MeOH/CH₂ Cl₂, to providethe title compound (86 mg, 56%): m.p. 93° (EtOAc/Et₂ O); ¹ H NMR (300MHz, CDCl₃) δ 7.85 (dd, J=2, 3 Hz, 1H), 7.36 (ddd, J=3, 6, 9 Hz, 1H),6.90 (dd, J=3, 9 Hz, 1H), 4.67 (m, 4H), 4.18 (m, 2H), 4.08. dt (5, J=9Hz, 1H), 3.95 (m, 1H), 2.68 (m, 1H), 2.39 (m, 1H); MS (APCI) m/e 265((M+1)); Analysis calc'd for C₁₃ H₁₃ N₂ O₃ F: C, 59.08; H, 4.95; N,10.60; found: C, 58.90; H, 4.88; N, 10.52.

Example 75 1-(5,5-dimethyl-3-oxocyclohexenyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 65% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) byreaction with 5,5-dimethyl-1,3-cyclohexanedione according to theprocedure of Example 74. ¹ H NMR (300 MHz, CDCl₃) δ 7.85 (dd, J=2, 3 Hz,1H), 7.35 (ddd, J=3, 6, 9 Hz, 1H), 6.87 (dd, J=3, 9 Hz, 1H), 5.02 (m,1H), 4.62 (m, 1H), 4.29 (m, 1H), 4.15 (m, 1H), 4.05 (m, 1H), 3.91 (m,1H), 2.59 (m, 1H), 2.37 (m, 1H), 2.14 (br s, 2H), 2.09 (m, 2H), 1.05 (s,3H), 1.03 (s, 3H); MS (DCI/NH₃) m/e 305 ((M+1)); Analysis calc'd for C₁₇H₂₁ N₂ O₂ F.0.75 H₂ O: C, 64.23; H, 7.13; N, 8.81; found: C, 63.89; H,7.03; N, 8.73.

Example 76 1-(3-oxocyclohexenyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 77% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) byreaction with 5,5-dimethyl-1,3-cyclohexanedione according to theprocedure of Example 74. ¹ H NMR (300 MHz, CDCl₃) δ 7.84 (dd, J=2, 3 Hz,1H), 7.35 (ddd, J=3, 6, 9 Hz, 1H), 6.87 (dd, J=3, 9 Hz, 1H), 5.01 (m,1H), 4.61 (m, 1H), 4.26 (m, 1H), 4.13 (m, 1H), 4.04 (m, 1H), 3.92 (m,1H), 2.58 (m, 1H), 2.37 (m, 1H), 2.27 (m, 4H), 1.94 (m, 2H); MS(DCI/NH₃) m/e 277 ((M+1)); Analysis calc'd for C₁₅ H₁₇ N₂ O₂ F.0.75 H₂O: C, 62.16; H, 6.43; N, 9.66; found: C, 62.15; H, 6.30; N, 9.67.

Example 77 1-(2,2-bis(ethoxycarbonyl)ethenyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 81% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) byreaction with diethyl ethoxymethylenemalonate according to the procedureof Example 74 and warming for 20 hours. ¹ H NMR (300 MHz, CDCl₃) δ 7.85(m, 1H), 7.67 (br s, 1H), 7.36 (ddd, J=3, 6, 9 Hz, 1H), 6.87 (dd, J=3, 9Hz, 1H), 4.79 (m, 1H), 4.29 (m, 1H), 4.17 (m, 6H), 4.02 (m, 1H), 2.58(m, 1H), 2.26 (m, 1H), 1.30 (t, J=7 Hz, 3H), 1.26 (t, J=7 Hz, 3H); MS(DCI/NH₃) m/e 353 (M+1); Analysis calc'd for C₁₇ H₂₁ N₂ O₅ F: C, 57.94;H, 6.00; N, 7.95; found: C, 57.63; H, 6.05; N, 7.77.

Example 78 1-(ethoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

To a solution of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate(from Example 8, 0.2 g, 0.56 mmol) in CH₂ Cl₂ (10 mL) and 10 ml ofNaHCO₃ solution was added ethyl chloroformate (0.064 g, 0.59 mmol). Thereaction mixture was stirred at room temperature for 2 hours. Theorganic layer was separated, dried (MgSO₄) and evaporated. The residuewas chromatographed on silica gel eluting with 1:1 EtOAc:hexane to yield0.09 g (63%) of the title compound: ¹ H NMR (300 MHz, CDCl₃) δ 7.87 (m,1H), 7.28 (ddd, J=3, 6, 9 Hz, 1H), 6.86 (dd, J=3, 9 Hz, 1H), 4.59 (m,1H), 4.26 (m, 1H), 4.14 (m, 1H), 4.10 (q, J=7 Hz, 2H), 3.96 (t, J=8 Hz,2H), 2.38 (m, 2H), 1.22 (t, J=7 Hz, 3H); MS (DCI/NH₃) m/e 255; Analysiscalc'd for C₁₂ H₁₅ N₂ O₃ F: C, 56.69; H, 5.95; N, 11.02; found: C,56.40; H, 5.78; N, 10.92.

Example 79 1-(phenoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 83% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) bythe procedure of Example 78, except substituting phenyl chloroformatefor the ethyl chloroformate thereof. ¹ H NMR (300 MHz, CDCl₃) δ 7.90(dd, J=2, 3 Hz, 1H), 7.35 (m, 3H), 7.18 (m, 1H), 7.06 (br d, J=8 Hz,2H), 6.86 (dd, J=3, 9 Hz, 1H), 4.73 (m, 1H), 4.46 (dd, J=4, 10 Hz, 1H),4.12 (m, 3H), 2.48 (m, 2H); MS (DCI/NH₃) m/e 303; Analysis calc'd forC₁₆ H₁₅ N₂ O₃ F: C, 63.57; H, 5.00; N, 9.27; found: C, 63.82; H, 4.86;N, 8.99.

Example 80 1-(4-nitrophenoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 82% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) bythe procedure of Example 78, except substituting 4-nitrophenylchloroformate for the ethyl chloroformate thereof: m.p. 68-70°; ¹ H NMR(300 MHz, CDCl₃) δ 8.22 (m, 2H), 7.91 (m, 1H), 7.39 (ddd, J=3, 6, 9 Hz,1H), 7.27 (m, 2H), 6.88 (dd, J=3, 9 Hz, 1H), 4.76 (m, 1H), 4.47 (m, 1H),4.19 (m, 3H), 2.52 (m, 2H); MS (DCI/NH₃) m/e 348; [α]_(D) ²⁰ 11.18°(c=0.004, CH₂ Cl₂); Analysis cal'd for C₁₆ H₁₄ N₃ O₅ F: C, 55.33; H,4.06; N, 12.10; found: C, 54.95; H, 4.00; N, 11.96.

Example 81 1-(4methoxyphenoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 65% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) bythe procedure of Example 78, except substituting 4-methoxyphenylchloroformate for the ethyl chloroformate thereof: m.p. 60-61°; ¹ H NMR(300 MHz, CDCl₃) δ 7.90 (m, 1H), 7.40 (ddd, J=3, 6, 9 Hz, 1H), 6.97 (brd, J=9 Hz, 2H), 6.86 (m, 3H), 4.72 (m, 1H), 4.46 (dd, J=4, 10 Hz, 1H),4.15 (m, 3H), 3.77 (s, 3H), 2.48 (m, 2H); MS (DCI/NH₃) m/e 333; [α]_(D)²⁰ 9.11° (c=0.0047, CH₂ Cl₂); Analysis calc'd for C₁₇ H₁₇ N₂ O₄ F: C,61.44; H, 5.16; N, 8.43; found: C, 61.39; H, 5.11; N, 8.22.

Example 82 1-(4-(methoxycarbonyl)phenoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 84% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) bythe procedure of Example 78, except substituting4-(methoxycarbonyl)phenyl chloroformate for the ethyl chloroformatethereof: mp 90-92° C.; ¹ H NMR (300 Mhz, CDCl₃) δ 8.13 (m, 2H), 7.9 (m,1H), 7.4 (m, 1H), 7.15 (d, 2H), 6.88 (dd, 1H), 4.73 (m, 1H), 4.48 (m,1H), 4.18 (m, 3H), 3.9 (s,3H), 2.5 (m, 2H); MS (CI/NH₃) m/e 361 (M+1),378 (M+NH₄).

Example 83 1-(4-methylphenoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 96% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) bythe procedure of Example 78, except substituting 4-methylphenylchloroformate for the ethyl chloroformate thereof: mp 68-70° C.; ¹ H NMR(300 MHz, CDCl₃) δ 7.9 (m, 1H), 7.4 (m, 1H), 7.12 (d, 2H), 6.93 (d, 2H),6.86 (dd, 1H), 4.71 (m, 1H), 4.45 (m, 1H), 4.13(m, 3H), 2.47 (m, 2H),2.3 (s, 3H); MS (CI/NH₃) m/e 317 (M+1), 334 (M+NH₄).

Example 84 1-(4-fluorophenoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 72% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) bythe procedure of Example 78, except substituting 4-fluorophenylchloroformate for the ethyl chloroformate thereof: ¹ H NMR (300 MHz,CDCl₃) δ 7.9 (m, 1H), 7.4 (m, 1H), 7.2 (d, 4H), 6.88 (dd, 1H), 4.73(m,1H), 4.48 (m, 1H), 4.18 (m, 3H), 2.5 (m, 2H); MS (CI/NH₃) m/e 321 (M+1),338 (M+NH₄).

Example 85 1-(4-chlorophenoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 85% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) bythe procedure of Example 78, except substituting 4-chlorophenylchloroformate for the ethyl chloroformate thereof: ¹ H NMR (300 MHz,CDCl₃) δ 7.9 (m, 1H), 7.4 (m, 1H), 7.3 (m, 2H), 7.02 (m, 2H), 6.87 (dd,1H), 4.73 (m, 1H), 4.47 (m, 1H), 4.17 (m, 3H), 2.5 (m, 2H); MS (CI/NH₃)m/e 337 (M+1), 354 (M+NH₄).

Example 86 1-(2,6-dimethylphenoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 43% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example 8) bythe procedure of Example 78, except substituting 2,6-dimethylphenylchloroformate for the ethyl chloroformate thereof: ¹ H NMR (300 MHz,CDCl₃) δ 7.9 (m, 1H), 7.4 (m, 1H), 7.03 (s, 3H), 6.88 (dd, 1H), 4.73 (m,1H), 4.5 (m, 1H), 4.18 (m, 3H), 2.5 (m, 2H), 2.15 (bs, 6H); MS (CI/NH₃)m/e 331 (M+1), 348 (M+NE₄).

Example 87 1-(2-methylphenoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared as a colorless oil in quantitative yieldfrom 5-(2R)-azetidinylmethoxy)-2-fluoropyridine tosylate (from Example8) by the procedure of Example 78, except substituting 2-methylphenylchloroformate for the ethyl chloroformate thereof: ¹ H NMR (CDCl₃) δ8.13 (m, 2H), 7.9 (m, 1H), 7.4 (m, 1H), 7.15 (d, 2H), 6.88 (dd, 1H),4.73 (m, 1H), 4.5 (m, 1H), 4.18 (m, 3H), 2.5 (m, 2H), 2.15 (s, 3H); MS(CI/NH₃) m/e 317 (M+1), 334 (M+NH₄).

Example 88 1-(1-acetoxy-1-methyl)ethoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

88a. Isopropenyl p-nitrophenyl carbonate

Isopropenyl chloroformate (5.0 g, 41.5 mmol) was added to an ice coldsuspension of p-nitrophenol (6.3 g, 45.6 mmol) in chloroform (100 mL).To the stirred reaction mixture, pyridine (3.32 g, 41.5 mmol) was addeddropwise over 20 minutes. After stirring at ice bath temperature for 15minutes, the reaction mixture was allowed to warm up and stirred at roomtemperature for 16 hours. The reaction mixture was washed with water, 1NHCl, ice-cold 1% aqueous sodium hydroxide, water and brine. The organiclayer was dried (MgSO₄) and the solvent was evaporated. The solidresidue was subsequently crystallized from hexane to provide the titlecompound (7.8 g, 84% yield): ¹ H NMR (CDCl₃, 300 MHz) δ 2.05 (s, 3H),4.82 (t, 1H, J=1.0 Hz), 4.96 (d, 1H, J=2.0 Hz), 7.40-7.46 (m, 2H),8.27-8.32 (m, 2H).

88b. 2-Chloro2-propyl p-nitrophenyl carbonate

The isopropenyl carbonate from step 88a (7.5 g, 33.6 mmol) was dissolvedin a mixture of ethyl ether (100 mL) and chloroform (100 mL). Themixture was cooled to 0° C. and then bubbled with HCl gas. Afterstanding at room temperature for 16 hours the mixture was purged withnitrogen to remove the excess HCl, and the solvent was evaporated togive the title compound (8.0 g, 92%): ¹ H NMR (CDCl₃, 300 MHz) δ 2.11(s, 6H), 7.39-7.44 (m, 2H), 8.27-8.32 (m, 2H).

88c. 2-Acetoxy-2-propyl p-nitrophenyl carbonate

A mixture of 2-chloro-2-propyl p-nitrophenyl carbonate (8.0 g, 30.8mmol) and mercuric acetate (11.0 g, 34.6 mmol) in dichloromethane (400mL) was stirred at room temperature for 72 hours. The reaction mixturewas washed with brine containing a few drops of sodium bicarbonatesolution and then with aqueous sodium bicarbonate. The organic layer wasdried (MgSO₄) and evaporated to afford an oil (5.4 g, 62%). ¹ H NMR(CDCl₃, 300 MHz) δ 1.93 (s, 6H), 2.10 (s, 3H), 7.37-7.42 (m, 2H),8.26-8.31 (m, 2H).

88d. 1-(1-acetoxy-1-methyl)ethoxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2- fluoropyridine

A solution of 3-(2-(R)-azetidinylmethoxy-6-fluoro-pyridine (from Example8, 0.30 g, 1.65 mmol) and the 2-acetoxy-2-propyl p-nitrophenyl carbonatefrom step 88c (0.49 g, 1.73 mmol) in dimethylformamide (6 mL) wasstirred at room temperature for 24 hours. The reaction mixture wasdiluted with water (25 mL) and extracted with ethyl acetate. The organiclayer was washed with water, ice cold 1% aqueous sodium hydroxide, 1NHCl water and brine, and then dried (MgSO₄) and concentrated. Theresidue was chromatographed to afford an light yellow oil (0.175 g,33%): ¹ H NMR (300 MHz, CDCl₃) δ 7.88 (s, 1H), 7.40 (m, 1H), 6.86 (dd,J=3.7, 8.8 Hz, 1H), 4.57 (m, 1H), 4.34 (m, 1H), 4.14 (m, 1H), 3.95 (t,J=7.5 Hz, 2H), 2.34-2.44 (m, 2H), 2.01 (s, 3H), 1.98 (s, 3H), 1.79 (s,3H); MS (DC/NH₃) m/e 327 ((M+1)); [α]_(D) ²⁰ +74.5° (c=0.2, MeOH);Analysis calc'd for C₁₅ H₁₉ N₂ O₅ F: C, 54.81; H, 5.60; N, 8.26; found:C, 55.21; H, 5.87; N, 8.58.

Example 89 1-((5-methyl-2-oxo-1,3-dioxol-4-en-4-yl)methoxycarbonyl)prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

A sample of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example 8(0.13 g, 0.7 mmol)) and (5-methyl-2-oxo-1,3-dioxol4-en-4-yl)methylp-nitrophenyl carbonate (prepared according to J. Alexander, et al., J.Med. Chem. 1996, 39, 480-486) (0.21 g, 0.73 mmol) in DMF (2 ml) wasstirred at room temperature for 16 hours. The reaction mixture wasdiluted with water and extracted with EtOAc. The organic layer waswashed with with water, 1N HCl, 2% sodium carbonate and brine. It wasdried over MgSO₄ and evaporated. The residue was chromatographed onsilica gel eluting with 30% EtOAc/hexane to yield 0.17 g (72%) ofproduct: ¹ H NMR (300 MHz, CDCl₃) δ 7.86 (m, 1H), 7.36 (ddd, J=3, 6, 9Hz, 1H), 6.87 (dd, J=3, 9 Hz, 1H), 4.80 (m, 2H), 4.61 (m, 1H), 4.36 (m,1H), 4.11 (dd, J=3, 10 Hz, 1H), 3.99 (m, 2H), 2.42 (m, 2H), 2.15 (s,3H); MS (DCI/NH₃) m/e 339, 183; [α]_(D) ²⁰ +6.43° (c=0.0042, CH₂ Cl₂);Analysis calc'd for C₁₅ H₁₅ N₂ O₆ F: C, 53.26; H, 4.47; N, 8.28; found:C, 53.52; H, 4.58; N, 8.15.

Example 90 1-((5-methyl-2-oxo-1,3-dioxo-4-en-4-yl)methoxycarbonyl)prodrug of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 61% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example 8) by theprocedure of Example 450, except substituting5-phenyl-2-oxo-1,3-dioxolan-4-ylmethyl p-nitrocarbonate (J. Alexander etal., J. Med. Chem. 1996, 39, 480-486) for the(5-methyl-2-oxo-1,3-dioxol4-en4-yl)methyl p-nitrophenyl carbonatethereof: ¹ H NMR (300 MHz, CDCl₃) δ 7.85 (m, ¹ H), 7.59 (m, 2H), 7.44(m, 3H), 7.35 (m, 1H), 6.84 (dd, J=3, 9 Hz, 1H), 5.09 (m, 2H), 4.63 (m,1H), 4.37 (m, 1H), 4.11 (dd, J=3, 10 Hz, 1H), 4.03 (m, 2H), 2.44 (m,2H); MS (DCI/NH₃) m/e 401, 194; [α]_(D) ²⁰ +3.07° (c=0.0035, CH₂ Cl₂);Analysis calc'd for C₂₀ H₁₇ N₂ O₆ F: C, 60.00; H, 4.28; N, 7.00; found:C, 59.81; H, 4.30; N, 6.98.

Example 91 1-((pyrrolidin-1-yl)carbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

A solution of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example8, 0.09 g, 0.49 mmol) and pyrrolidine carbonyl chloride (0.073 g, 0.54mmol) in toluene (10 mL) was refluxed for 5 hours. The reaction mixturewas evaporated and partitioned in CH₂ C₂ /H₂ O. The organic layer wasdried (MgSO₄) and concentrated. The residue was chromatographed onsilica gel, eluting with EtOAc to yield 0.07 g (51%) of product: ¹ H NMR(300 MHz, CDCl₃) δ 7.86 (m, 1H), 7.38 (m, 1H), 6.85 (m, 1H), 4.5-4.8 (m,2H), 3.8-4.2 (m, 3H), 3.33 (m, 4H), 2.36 (m, 2H), 1.84 (m, 4H); MS(DCI/NH₃) m/e 280, 169; [α]_(D) ²⁰ +6.57° (c=0.0026, CH₂ Cl₂); Analysiscalc'd for C₁₄ H₁₈ N₃ O₂ F.0.75 H₂ O: C, 57.42; H, 6.71; N, 14.35;found: C, 57.51; H, 6.43; N, 14.36.

Example 92 1-((pyrrolidin-1-yl)carbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

The title compound was prepared in 46% yield from5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example 8) by theprocedure of Example 91, except substituting diethylcarbamyl chloridefor the pyrrolidine carbonyl chloride thereof: ¹ H NMR (300 MHz, CDCl₃)δ 7.87 (m, 1H), 7.39 (ddd, J=3, 6, 9 Hz, 1H), 6.82 (dd, J=3, 9 Hz, 1H),4.72 (m, 1H), 4.20 (dd, J=5, 10 Hz, 1H), 4.10 (dd, J=3, 10 Hz, 1H), 3.96(m, 1H), 3.84 (m, 1H), 3.18 (m, 4H), 2.33 (m, 2H), 1.09 (t, J=7 Hz, 6H);MS (DCI/NH₃) m/e 282; [α]_(D) ²⁰ +2.66° (c=0.005, CH₂ Cl₂); Analysiscalc'd for C₁₄ H₂₀ N₃ O₂ F: C, 59.77; H, 14.94; found: C, 59.65; H,7.04; N, 14.90.

Example 93 1-(acetyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example 8, 162 mg, 0.89mmole), acetic anhydride (0.12 mL, 1.26 mmole), TEA (0.2 mL 1.47 mmole),and CH₂ Cl₂ (30 mL) were combined under N₂ and stirred for 16 hours. Thesolution was extracted with sat. aq. Na₂ CO₃ (30 mL), brine (2×30 mL)and dried (MgSO₄). The solvent was evaporated under vacuum and the crudeproduct was chromatographed (silica gel; hexane/EtOAc 9:1 to 7:3) toyield 160 mg (80%) of the title compound: ¹ H NMR (DMSO-d₆, 300 MHz) δ:1.74 (s, 3H), 2.16 (m, H), 2.40 (m, ¹ H), 3.86 (br s, 2H), 4.25(dd,J=3.5, 10.5, 1H), 4.36 (d,J=4.5, 10.5 1H), 4.58 (br s, 1H), 7.01(dd, J=3.5, 8.5, 1H), 7.57 (m, 1H), 7.90 (m, 1H); MS (CI/NH₃) m/e 225(M+H)⁺ 242 (M+NH₄)⁺ ; [α]_(D) +91.7 (c 1, MeOH); Anal. calcd. for C₁₁H₁₃ FN₂ O₂.0.2 C₄ H₈ O₂. C, 58.6 H, 6.08;N, 11.58; found: C, 58.27; H,6.04; N, 11.63.

Example 94 1-(t-butyloxycarbonyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

A solution of 5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example8, 0.12 g, 0.7 mmol), di-t-butyl-dicarbonate (0.23 g, 1 mmol) and DMAP(0.13 g, 1 mmol) in CH₂ Cl₂ (10 mL) was stirred at room temperature for16 hours. The mixture was evaporated and the residue chromatographed onsilica gel eluting with EtOAc/hexane 1:1 to yield 0.14 g (71%) ofproduct: ¹ H NMR (300 MHz, CDCl₃) δ 7.87 (m, 1H), 7.38 (ddd, J=3, 6,9Hz, 1H), 6.85 (dd, J=3, 9 Hz, 1H), 4.50 (m, 1H), 4.31 (m, 1H), 4.12 (dd,J=3, 10 Hz, 1H), 3.89 (t, J=8 Hz, 2H), 2.33 (m, 2H), 1.42 (s, 9H); MS(DCI/NH₃) m/e 283, 227; Analysis calc'd for C₁₄ H₁₉ N₂ O₃ F: C, 59.56;H, 6.78; N, 9.92; found: C, 59.34; H, 6.65; N,

Example 95 disulfide prodrug dimer of 1-(3-thiopropionyl)5-(2R)-azetidinylmethoxy)-2-fluoropyridine

To a solution of 3,3'-dithiodipropionic acid (100 mg, 0.48 mmol) andtriethylamine (53 mg, 0.53 mmol) in THF (1.0 mL) at -78° C. was addedisobutyl chloroformate (68 mg, 0.51 mmol) dropwise with stirring. Afterstirring at -78° C. for 1 hour,5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example 8, 175 mg, 0.96mmol) was added to the reaction mixture. The resultant solution wasallowed to warm to 25° C. and stirred for 3 hours. After all of thestarting material was consumed, the organic solvent was evaporated undervacuum. The residue was purified by column silica gel chromatographyeluting with ethyl acetate:hexane (1:1) to provide the title compound(102 mg, 21%). ¹ H NMR (300 MHz, CDCl₃) δ 2.32-2.65 (m, 8H), 2.79-2.97(m, 4H), 3.89-4.27 (m, 6H), 4.50 (dd, J=4.4 Hz, 9.8H, 2H), 4.61-4.83 (m,1H), 6.85 (dd, J=3.8 Hz, 8.2H, 2H), 7.37 (m, 2H), 7.87 (m, 2H); MS(DCI/NH₃) m/e 539 (M+1); [α]_(D) ²⁰ +101° (c=0.10, MeOH; Analysis calc'dfor C₂₄ H₂₈ N₄ O₂ F₂ S₂.0.5 CHCl₃ : C, 51.96; H, 5.07; N, 9.89; found:C, 52.13; H, 5.40; N, 10.25.

Example 96 1-(S-(phenylmethyl)cysteinoyl) prodrug of5-(2R)-azetidinylmethoxy)-2-fluoropyridine

To a solution of S-benzyl-N-Cbz-(L)-cysteine and triethylamine in THF at-78° C. was added isobutyl chloroformate dropwise with stirring. Afterstirring at -78° C. for 1 hour,5-(2R)-azetidinylmethoxy)-2-fluoropyridine (from Example 8, 175 mg, 0.96mmol) was added to the reaction mixture. The resultant solution allowedto warm to 25° C. and stirred for 3 hours. After all of the startingmaterial was consumed, the organic solvent was evaporated under vacuum.The residue was N-deprotected and purified by column silica gelchromatography eluting with ethyl acetate:hexane (1:1) to provide thetitle compound. ¹ H NMR (300 MHz, CDCl₃) δ 7.16-7.40 (m, 6H), 7.86 (m,1H), 6.84 (m, 1H), 4.66 (m, 1H), 4.51 (m, 1H), 4.04-4.22 (m, 2H), 3.96(m, 1H), 3.75 (s, 2H), 3.38 (m, 1H), 2.74 (m, 1H), 2.58 (m, 1H),2.34-2.48 (m, 2H), 1.63-2.04 (m, 2H); MS (DCI/NH₃) m/e 376 (M+1)⁺ ;[α]_(D) ²⁰ +110° (c=0.05, MeOH); Analysis calc'd for C₁₉ H₂₂ N₃ O₂FS.0.1 H₂ O: C, 60.49; H, 5.93; N, 11.14; found: C, 60.11; H, 6.01; N,10.80.

Example 97 2-Chloro-3-(2-(R)-azetidinylmethoxy)pyridine tosylate

97a. 2-Chloro-3-(1-Boc-2-(R)-azetidinylmethoxy)pyridine

The procedures of examples 10c and 10d were used, substitutingBoc-(R)-hydroxymethylazetidine for the Boc-(S)-hydroxymethylazetidineused in step 10c, and 2-chloro-3-hydroxypyridine for3-fluoro-5-hydroxypyridine in step 10d. The title compound was obtainedas an oil (535 mg, 93%): ¹ H NMR (CDCl₃, 300 MHz) δ 1.40 (s, 9H), 2.40(m, 2H), 3.90-4.00(m, 2H), 4.16 (m, 1H), 4.55 (m, 2H), 7.20 (m, 1H),7.35 (m, 1H), 8.00 (m, 1H); MS (CI/NH₃) m/z: 299 (M+H)⁺.

97b. 2-Chloro-3-(2-(R)-azetidinylmethoxy)pyridine tosylate

The product of Example 459a (530 mg, 1.78 mmol) was treated accordingthe the procedure of example 407b. The residue was chromatographed(silica gel; CHCl₃ /MeOH, 95:5 to 90:10) to afford the free base of thetitle compound as white solid, which was converted to the salt bytreatment with p-toluenesulfonic acid in ethanol to give the titlecompound (398 mg). mp 102-104° C.; [α]²⁵ _(D) =+5.78° (c=0.74, MeOH); ¹H NMR (DMSO, 300 MHz) δ 2.28 (s, 3H), 2.52 (m, 2H), 2.62 (m, 1H), 3.98(m, 2H), 4.42 (d, J=3 Hz, 2H), 4.78 (br, 1H), 7.18 (d, J=9 Hz, 2H), 7.45(d, J=6 Hz, 1H), 7.52 (d, J=9 Hz, 2H), 7.64 (dd, J=3, 9 Hz, 1H), 8.05(dd, J=3, 6 Hz, 1H), 8.90 (br, 1H); MS (APCI) m/z 1.99 (M+H)⁺, 231(M+H+MeOH)⁺. Anal. calcd. for C₉ H₁₁ ClN₂ O.1.2 TsOH.0.5 H₂ O: C, 50.45;H, 5.25; N, 6.76. Found: C, 50.30; H, 5.15; N, 6.56.

Example 98 6-Fluoro-3-(1-methyl-2-(R)-azetidinylmethoxy)pyridinetosylate

98a. 1-Cbz-2-(R)-azetidinemethyl-p-toulenesulfonate

To a solution of 1-Cbz-2-(R)-azetidinemethanol (30.76 g, 218.8 mmol) inmethylene chloride (75 mL) at 0° C. was added triethylamine (25.2 mL 179mmol) and p-tolenesulfonyl chloride (34.46 g 181 mmol). The mixture wasstirred for 16 hours and filtered, then the filtrate was washed with 2Nsodium hydroxide (50 mL), 2N HCl (50 mL), brine and dried (MgSO₄). Thesolvent was evaporated under vacuum, and the crude product waschromatographed (silica gel; hexane/EtOAc 9:1 to 6:4) to yield 44.1 g(78.8%) of the title compound. ¹ H NMR (CDCl₃, 300 MHz) δ: 2.21-2.43 (m,3H), 2.45 (s,3H), 3.84-3.92 (m, 2H), 4.13 (m, 1H), 4.36 (m, 1H), 4.58(m, 1H), 5.0 (br. s 2H), 7.26-7.27 (m, 7H). MS (CI/NH₃) m/e 376 (M+H)⁺393 (M+NH₄)⁺. Anal. calcd. for C₁₉ H₂₁ NO₅ S. C, 60.78 H, 5.64;N, 3.73.Found: C, 60.40 H, 5.82; N, 3.75. [α]_(D) +53.06 (c 1.0, CHCl₃).

98b. 6-Fluoro-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine

The procedure of example 10d was used, substituting the product of step98a for t-butoxycarbonyl-(S)-toluensulfonyoxymethylazetidine and2-fluoro-5-hydroxypyridine from Example 8 for3-fluoro-5-hydroxypyridine. The product was obtained as a colorless oil:¹ H NMR (dmso-d₆, 300 MHz) δ: 2.21 (m, 1H), 2.38 (m, 1H), 3.87 (t, J=7Hz, 2H), 4.19 (dd, J=4, 11 Hz, 1H), 4.34 (dd J=4, 11 Hz, 1H), 4.54 (m,1H), 5.01 (m, 2H), 6.97 (dd, J=3, 9 Hz, 1H), 7.28 (m, 5H), 7.50 (m, 1H),7.85 (m, 1H). MS (CI/NH₃) m/e 317 (M+H)⁺. Anal. calcd. for C₁₇ H₁₇ FNO₃.C, 64.55, H, 5.42, N, 8.86 .Found: C, 64.57 H, 5.44; N, 8.83. [α]_(D)+74.6 (c 1.1, CHCl₃).

98c. 6-Fluoro-3-(1-methyl-2-(R)-azetidinylmethoxy)pyridine tosylate

6-Fluoro-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine from Example 98b (1g, 3.16 mmol) was combined with 10% Pd-C (50 mg) and paraformaldehyde (1g) in ethanol (10 mL), and the mixture was stirred under hydrogen (1atm) for 16 hours. The mixture was filtered and concentrated. Theresidue was taken up in ethyl acetate, treated with p-toluenesulfonicacid, and the resulting salt was crystallized from ethyl acetate-etherto provide the title compound (813 mg, 74%): m.p. 121-125°; ¹ H NMR (500MHz, D₂ O) δ 7.91 (m, ¹ H), 7.69 (d, J=8.4 Hz, 2H), 7.66 (m, 1H), 7.37(d, J=7.9 Hz, 2H), 7.10 (dd, J=2.7, 8.6 Hz, 1H), 4.86 (m, 1H), 4.45 (dd,J=2.4, 11.6 Hz, 1H), 4.37 (dd, J=5.5, 11.6 Hz, ¹ H), 4.27 (m, 1H), 4.00(q, J=10.2 Hz, 1H), 2.99 (s, 3H), 2.67 (m, 1H), 2.62 (m, 1H), 2.40 (s,3H); ¹⁹ F NMR (471 MHz, D₂ 0) δ -78.38; MS (CI/NH₃) m/e 197 (M+H)⁺ ;Analysis calc'd for C₁₇ H₂₁ N₂ O₄ FS: C, 55.42; H, 5.75; N, 7.60; found:C, 55.07; H, 5.79; N, 7.40.

Example 99 6-Fluoro-3-(1-ethyl-2-(R)-azetidinylmethoxy)pyridine tosylate

The title compound was prepared in 27% yield by the procedure of example98c starting with acetaldehyde in place of paraformaldehyde: m.p.106-109°; ¹ H NMR (500 MHz, D₂ O) δ 7.91 (m, 1H), 7.69 (d, J=8.0 Hz,2H), 7.66 (m, 1H), 7.37 (d, J=7.9 Hz, 2H), 7.11 (dd, J=2.8, 8.4 Hz, 1H),4.82 (m, 1H), 4.43 (m, 2H), 4.23 (m, 1H), 3.98 (q, J=9.7 Hz, 1H), 3.42(m, 1H), 3.30 (m, 1H), 2.64 (m, 2H), 2.40 (s, 3H), 1.24 (t, J=7.3 Hz,3H); ¹⁹ F NMR (471 MHz, D₂ O) δ -78.38; MS (CI/NH₃) m/e 211 (M+H)⁺ ;Analysis calc'd for C₁₈ H₂₃ N₂ O₄ FS: C, 56.53; H, 6.06; N, 7.32; found:C, 56.28; H, 5.97; N, 7.20.

Example 100 6-Fluoro-3-(1-propyl-2-(R)-azetidinylmethoxy)pyridinetosylate

The title compound was prepared in 40% yield by the procedure of example98c starting with propanal in place of paraformaldehyde: m.p. 93-95°; ¹H NMR (500 MHz, D₂ O) δ 7.92 (m, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.66 (m,1H), 7.38 (d, J=8.0 Hz, 2H), 7.11 (dd, J=2.5, 9.2 Hz, 1H), 4.84 (m, 1H),4.44 (m, 2H), 4.23 (m, 1H), 4.01 (m, 1H), 3.34 (m, 1H), 3.20 (m, 1H),2.63 (q, J=8.5 Hz, 2H), 2.40 (s, 3H), 1.66 (m, 2H), 0.96 (t, J=7.8 Hz,3H); ¹⁹ F NMR (471 MHz, D₂ O) δ -78.35; MS (CI/NH₃) m/e 225 (M+H)⁺ ;Analysis calc'd for C₁₉ H₂₅ N₂ O₄ FS: C, 57.56; H, 6.36; N, 7.07; found:C, 57.37; H, 6.13; N, 6.82.

Example 1016-Fluoro-3-(1-(1-methylethyl)-2-(R)-azetidinylmethoxy)pyridine tosylate

The title compound was prepared in 22% yield by the procedure of example98c starting with acetone in place of paraformaldehyde: m.p. 93-95°; ¹ HNMR (500 MHz, D₂ O) δ 7.88 (m, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.64 (m,1H), 7.35 (d, J=7.9 Hz, 2H), 7.09 (dd, J=2.6, 8.5 Hz, 1H), 4.85 (m, 1H),4.39 (m, 2H), 4.14 (m, 1H), 4.02 (q, J=9.5 Hz, 1H), 3.58 (hept, J=6.7Hz, 1H), 2.58 (m, 2H), 2.38 (s, 3H), 1.31 (d, J=6.7 Hz, 3H), 1.25 (d,J=6.7 Hz, 3H); ¹⁹ F NMR (471 MHz, D₂ O) δ -78.42; MS (CI/NH₃) m/e 225(M+H)⁺ ; Analysis calc'd for C₁₉ H₂₅ N₂ O₄ FS.0.1 CH₃ OH: C, 57.19; H,6.29; N, 6.77; found: C, 56.98; H, 6.38; N, 6.94.

Example 102 6-Fluoro-3-(1-butyl-2-(R)-azetidinylmethoxy)pyridinetosylate

The title compound was prepared in 83% yield by the procedure of example98c starting with butanal in place of paraformaldehyde: m.p. 93-97°; ¹ HNMR (500 MHz, D₂ O) δ 7.91 (m, 1H), 7.69 (d, J=8.1 Hz, 2H), 7.65 (m,1H), 7.37 (d, J=8.5 Hz, 2H), 7.10 (dd, J=3, 9 Hz, 1H), 4.81 (m, 1H),4.42 (br, 2H), 4.23 (m, 1H), 4.00 (m, 1H), 3.35 (m, 1H), 3.25 (m, 1H),2.62 (m, 2H), 2.40 (s, 3H), 1.61 (m, 2H), 1.37 (m, 2H), 0.91 (t, J=7.3Hz, 3H); ¹⁹ F NMR (471 MHz, D₂ O) δ -78.32; MS (CI/NH₃) m/e 239 (M+H)⁺ ;Analysis calc'd for C₂₀ H₂₇ N₂ O₄ FS: C, 58.52; H, 6.63; N, 6.82; found:C, 58.23; H, 6.68; N, 6.72.

Example 103 6-Fluoro-3-(1-(2-methylpropyl)-2-(R)-azetidinylmethoxy)pyridine tosylate

The title compound was prepared in 43% yield by the procedure of example98c starting with isobutyraldehyde in place of paraformaldehyde: m.p.103-104°; ¹ H NMR (500 MHz, D₂ O) δ 7.91 (br, 1H), 7.69 (d, J=8.6 Hz,2H), 7.66 (m, 1H), 7.37 (d, J=7.9 Hz, 2H), 7.11 (dd, J=3, 9 Hz, 1H),4.86 (m, 1H), 4.44 (br, 2H), 4.26 (m, 1H), 4.04 (m, 1H), 3.30 (m, 1H),3.07 (dd, J=9.2, 12.8 Hz, 1H), 2.62 (m, 2H), 2.40 (s, 3H), 2.04 (m, 1H),0.98 (d, J=7.3 Hz, 3H), 0.96 (d, J=7.3 Hz, 3H); ¹⁹ F NMR (471 MHz, D₂ O)δ -78.3; MS (DCI/NH₃) m/e 239 (M+H)⁺ ; Analysis calc'd for C₂₀ H₂₇ N₂ O₄FS: C, 58.52; H, 6.63; N, 6.82; found: C, 58.36; H, 6.58; N, 6.77.

Example 104 6-Fluoro-3-(1-pentyl-2-(R)-azetidinylmethoxy)pyridinetosylate

The title compound was prepared in 64% yield by the procedure of example472c starting with pentanal in place of paraformaldehyde: m.p. 77-79°; ¹H NMR (500 MHz, D₂ O) δ 7.90 (br, 1H), 7.69 (d, J=7.9 Hz, 2H), 7.65 (m,1H), 7.37 (d, J=8.6 Hz, 2H), 7.11 (dd, J=2.6, 8.5 Hz, 1H), 4.82 (m, 1H),4.42 (br s, 2H), 4.23 (m, 1H), 4.01 (m, 1H), 3.35 (m, 1H), 3.23 (m, 1H),2.62 (q, J=8.5 Hz, 2H), 2.40 (s, 3H), 1.62 (m, 2H), 1.31 (m, 4H), 0.86(m, 3H); ¹⁹ F NMR (471 MHz, D₂ 0) δ -78.3; MS (CI/NH₃) m/e 253 (M+H)⁺ ;Analysis calc'd for C₂₁ H₂₉ N₂ O₄ FS: C, 59.41; H, 6.89; N, 6.60; found:C, 59.25; H, 6.81; N, 6.48.

Example 105 6-Fluoro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridinetosylate

105a. 6-Fluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy

The procedure of example 98 was followed, except substituting1-Cbz-2-(S)-azetidinemethanol for the 1-Cbz-2-(R)-azetidinemethanolthereof. The product was obtained as a clear oil: ¹ H NMR (dmso-d₆, 300MHz) δ: 2.21 (m, 1H), 2.38 (m, 1H), 3.87 (t, J=7 Hz, 2H), 4.19 (dd, J=4,11 Hz, 1H), 4.34 (dd J=4, 11 Hz, 1H), 4.54 (m, 1H), 5.01 (m, 2H), 6.97(dd, J=3, 9 Hz, 1H), 7.28 (m, 5H), 7.50 (m, 1H), 7.85 (m, 1H). MS(CI/NH₃) m/e 317 (M+H)⁺. Anal. calcd. for C₁₇ H₁₇ FNO₃ : C, 64.55, H,5.42, N, 8.86 Found: C, 64.37 H, 5.30; N, 8.83. [α]_(D) -74.7 (c 1.0,CHCl₃).

105b. 6-Fluoro-3-(1-methyl-2-(S)-azetidinylmethoxy)pyridine tosylate

The title compound was prepared by the procedure of example 98c, exceptsubstituting 6-fluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine for theR enantiomer thereof. The product was obtained as a white solid: mp124-126° C.; [α]_(D) =+15.93 (c 0.5, MeOH); ¹ H NMR (300 MHz, D₂ O) δ7.92 (s, 1H), 7.68 (m, 3H), 7.38 (d, 2H, J=8.0 Hz), 7.11 (dd, 1H,J=2.5,8.5 Hz), 4.8 (br s, 1H), 4.45 (m, 2H), 4.27 (br s, 1H), 4.02 (brs, 1H), 2.99 (s, 3H), 2.68 (m, 2H), 2.40 (s, 3H); MS (CI/NH₃); m/z 197(M+H)⁺. Anal. Calcd for C₁₀ H₁₃ FN₂ O.TsOH: C, 55.42; H, 5.75; N, 7.60.Found: C, 55.33; H, 5.74; N, 7.59.

Example 106 6-Fluoro-3-(1-ethyl-2-(S)-azetidinylmethoxy)pyridinetosylate

The title compound was prepared in 47% yield by the procedure of example105b, substituting acetaldehyde for the paraformaldehyde therein. Theproduct was obtained as a white solid: m.p. 101-103°; ¹ H NMR (500 MHz,D₂ O) δ 7.91 (m, 1H), 7.69 (d, J=8 Hz, 2H), 7.66 (m, 1H), 7.37 (d, J=8Hz, 2H), 7.11 (dd, J=9, 2 Hz, 1H), 4.80 (m, 1H), 4.44 (m, 2H), 4.23 (m,1H), 3.98 (m, 1H), 3.42 (1), 3.30 (dq, J=12, 7 Hz, 1H), 2.63 (br q, J=8Hz, 2H), 2.40 (s, 3H), 1.24 (t, J=7 Hz, 3H); ¹⁹ F NMR (471 MHz, D₂ O) δ-78.36; MS (DCI/NH₃) m/e 211 (M+1)⁺ ; Analysis calc'd for C₁₈ H₂₃ N₂ O₄FS: C, 56.53; H, 6.06; N, 7.32; found: C, 56.54; H, 6.05; N, 7.26.

Example 107 6-Fluoro-3-(1-propyl-2-(S)-azetidinylmethoxy)pyridinetosylate

The title compound was prepared in 74% yield by the procedure of example105b, substituting propanal for the paraformaldehyde thereof. Theproduct was obtained as a white solid: m.p. 95-104°; ¹ H NMR (500 MHz,D₂ O) δ 7.90 (m, 1H), 7.68 (d, J=8 Hz, 2H), 7.65 (m, 1H), 7.36 (d, J=8Hz, 2H), 7.10 (dd, J=9, 2 Hz, 1H), 4.81 (m, 1H), 4.41 (m, 2H), 4.23 (m,1H), 4.00 (q, J=10 Hz, 1H), 3.34 (m, 1H), 3.20 (m, 1H), 2.62 (m, 2H),2.39 (s, 3H), 1.65 (m, 2H), 0.95 (t, J=7 Hz, 3H); ¹⁹ F NMR (471 MHz, D₂O) δ -78.34; MS (CI/NH₃) m/e 225 (M+1)⁺ ; Analysis calc'd for C₁₉ H₂₅ N₂O₄ FS: C, 57.56; H, 6.36; N, 7.07; found: C, 57.51; H, 6.27; N, 6.90.

Example 108 6-Fluoro-3-(1-butyl-2-(S)-azetidinylmethoxy)pyridinetosylate

The title compound was prepared in 82% yield by the procedure of example105b, substituting butanal for the paraformaldehyde thereof. The productwas obtained as a white solid: m.p. 88-93°; ¹ H NMR (500 MHz, D₂ O) δ7.90 (m, 1H), 7.69 (d, J=8 Hz, 2H), 7.65 (m, 1H), 7.37 (d, J=8 Hz, 2H),7.10 (dd, J=9, 2 Hz, 1H), 4.81 (m, 1H), 4.42 (m, 2H), 4.22 (m, 1H), 4.00(q, J=9 Hz, 1H), 3.37 (m, 1H), 3.25 (m, 1H), 2.62 (m, 2H), 2.40 (s, 3H),1.61 (m, 2H), 1.37 (hex, J=7 Hz, 2H), 0.91 (t, J=7 Hz, 3H); ¹⁹ F NMR(471 MHz, D₂ O) δ -78.31; MS (CI/NH₃) m/e 239 (M+1)⁺ ; Analysis calc'dfor C₂₀ H₂₇ N₂ O₄ FS: C, 58.52; H, 6.63; N, 6.82; found: C, 58.28; H,6.64; N, 6.60.

Example 1096-Fluoro-3-(1-(2-methylpropyl)-2-(S)-azetidinylmethoxy)pyridine tosylate

The title compound was prepared in 83% yield by the procedure of example105b, substituting isobutyraldehyde for the paraformaldehyde. Theproduct was obtained as a white solid: m.p. 104-106°; ¹ H NMR (500 MHz,D₂ O) δ 7.91 (m, 1H), 7.70 (d, J=8 Hz, 2H), 7.66 (m, 1H), 7.37 (d, J=8Hz, 2H), 7.11 (dd, J=9, 2 Hz, 1H), 4.86 (m, 1H), 4.45 (m, 2H), 4.25 (m,1H), 4.05 (m, 1H), 3.29 (m, 1H), 3.07 (dd, J=13, 9 Hz, 1H), 2.62 (m,2H), 2.40 (s, 3H), 2.05 (m, 1H), 0.97 (t, J=7 Hz, 6H); ¹⁹ F NMR (471MHz, D₂ O) δ -78.29; MS (DCI/NH₃) m/e 239 ((M+1)⁺); Analysis calc'd forC₂₀ H₂₇ N₂ O₄ FS: C, 58.52; H, 6.63; N, 6.82; found: C, 58.36; H, 6.68;N, 6.73.

Example 110 6-Fluoro-3-(1-pentyl-2-(S)-azetidinylmethoxy)pyridinetosylate

The title compound was prepared in 49% yield by the procedure of example105b, substituting pentanal for the paraformaldehyde thereof. Theproduct was obtained as a white solid: m.p. 71-73°; ¹ H NMR (500 MHz, D₂O) δ 7.91 (m, 1H), 7.69 (d, J=8 Hz, 2H), 7.66 (m, 1H), 7.37 (d, J=8 Hz,2H), 7.11 (m, 1H), 4.82 (m, 1H), 4.43 (m, 2H), 4.23 (m, 1H), 3.99 (m,1H), 3.36 (m, 1H), 3.24 (m, 1H), 2.62 (m, 2H), 2.40 (s. 3), 1.63 (m,2H), 1.32 (m, 4H), 0.87 (m 3); ¹⁹ F NMR (471 MHz, D₂ O) δ -78.31; MS(DCI/NH₃) m/e 253 ((M+1)⁺); Analysis calc'd for C₂₁ H₂₉ N₂ O₄ FS: C,59.41; H, 6.89; N, 6.60; found: C, 59.13; H, 6.86; N, 6.53.

Example 1116-Fluoro-3-(1-(1,1-dimethylpropyl)-2-(R)-azetidinylmethoxy)pyridinetosylate

111a.5-[1-(1,1-Dimethyl-2-propynyl)-(2S)-azetidinylmethoxy]-2-fluoro-pyridine

To a solution of 5-((2S)-azetidinylmethyloxy)-2-fluoropyridine (530 mg,2.91 mmol) and 3-chloro-3-methyl-1-butyne (0.654 mL, 5.82 mmol) in THF(6 mL) at room temperature was added a catalytic amount of copper(I)chloride (14 mg, 0.15 mmol), resulting in formation of a precipitate.The mixture was stirred for 1 hour, diluted with Et₂ O and washed with 1N aqueous HCl. The layers were separated, and the aqueous phase wasbasified with 15% aqueous NaOH (pH=12) and extracted with CH₂ Cl₂. TheCH₂ Cl₂ extracts were dried (Na₂ SO₄) and concentrated. Purification bychromatography (silica gel; 98:2 CH₂ Cl₂ /MeOH) afforded 290 mg (40%) ofthe title compound as a light yellow oil: [α]_(D) ²³ -93.8 (c 1.03, CH₂Cl₂); ¹ H NMR (CDCl₃) δ 1.21 (s, 3H), 1.29 (s, 3H), 2.02 (m, 1H), 2.14(m, 1H), 2.39 (s, 1H), 3.23-3.29 (m, 2H), 3.90-4.06 (m, 3H), 6.85 (dd,J=1.7, 8.8 Hz, 1H), 7.32 (m, 1H), 7.82 (dd, J=1.7, 3.1 Hz, 1H); MS(CI/NH₃) m/z 249 (M+H⁺).

111b.5-[1-(1-Dimethyl-2-1propynyl)-(2S)-azetidinylmethoxy]-2-fluoro-pyridinetosylate

To a solution of5-[1-(1,1-dimethyl-2-propynyl)-(2S)-azetidinylmethoxy]-2-fluoropyridine(58 mg, 0.23 mmol) from step 111a above in EtOH (3 mL) was addedp-toluenesulfonic acidemonohydrate (44 mg, 0.23 mmol). The solution wasstirred for 1 hour, then the volatiles were removed under vacuum. Thesolid was triturated with Et₂ O then dried under high vacuum to afford93 mg (95%) of the the title compound as a white solid: mp 155-157° C.;¹ H NMR (D₂ O) δ 1.55 (s, 3H), 1.62 (s, 3H), 2.40 (s, 3H), 2.55 (m, 2H),3.26 (s, 1H), 4.06 (m, 1H), 4.21 (m, 1H), 4.42 (d, J=4.0 Hz, 2H), 5.05(m, 1H), 7.10 (dd, J=2.6, 8.8 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.67 (m,1H), 7.70 (d, J=8.5 Hz, 2H), 7.91 (m, 1H); MS (CI/NH₃) m/z 249 (M +H⁺).Anal. Calcd for C₁₄ H₁₇ FN₂ O.C₇ H₈ O₃ S: C, 59.98; H, 5.99; N, 6.66.Found: C, 59.78; H, 5.91; N, 6.52.

111c. 5-[1-(1,1-Dimethylpropyl)-(2S)-azetidinylmethoxy]-2-fluoropyridine

A suspension of5-[1-(1,1-dimethyl-2-propynyl)-(2S)-azetidinylmethoxy]-2-fluoropyridinefrom step 111b above (210 mg, 0.846 mmol) and 10% palladium on activatedcarbon (20 mg) in MeOH (10 mL) was stirred under an atmosphere ofhydrogen (balloon) for 18 hours. The catalyst was removed by filtrationthrough a pad of Celite (CH₂ Cl₂ wash), and the organic solution wasconcentrated to afford 206 mg of a yellow oil. Purification bychromatography (silica gel, 90:10 CH₂ Cl₂ /MeOH) afforded 190 mg (89%)of the title compound as a colorless oil: [α]_(D) ²³ -40.9 (c 1.13, CH₂Cl₂); ¹ H NMR (CDCl₃) δ 0.84 (t, J=7.1 Hz, 3H), 0.92 (s, 3H), 0.94 (s,3H), 1.30 (q, J=7.1 Hz, 2H), 1.95 (m, 1H), 2.07 (m, 1H), 3.10-3.35 (m,2H), 3.82 (m, 1H), 3.92-4.05 (m, 2H), 6.84 (m, 1H), 7.31 (m, ¹ H), 7.81(dd, J=2.4, 2.9 Hz, ¹ H); MS (CI/NH₃) m/z 253 (M +H⁺).

111d. 5-[1-(1,1-Dimethylpropyl)-(2S)-azetidinylmethoxy]-2-fluoropyridinetosylate

The free amine (84 mg, 0.33 mmol) from step 111c above was dissolved inEtOH (3 mL) and p-toluenesulfonic acidemonohydrate (63 mg, 0.33 mmol)was added. The solution was stirred for 2 hours, then the volatiles wereremoved under vacuum. The solid was triturated with Et₂ O then driedunder high vacuum to afford 145 mg (95%) of the the title compound as awhite solid: mp 84-86° C.; ¹ H NMR (D₂ O) δ 0.95 (t, J=7.3 Hz, 3H), 1.31(s, 3H), 1.37 (s, 3H), 1.68 (m, 2H), 2.40 (s, 3H), 2.54 (q, J=8.6 Hz,1H), 4.02 (m, 1H), 4.15 (m, 1H), 4.43 (m, 2H), 4.97 (m, 1H), 7.11 (dd,J=2.4, 9.2 Hz, 1H), 7.38 (d, J=7.9 Hz, 2H), 7.67 (m, 1H), 7.70 (d, J=8.6Hz, 2H), 7.91 (dd, J=1.2, 3.1 Hz, 1H); MS (CI/NH₃) m/z 253 (M +H⁺);Anal. Calcd for C₁₄ H₂₁ FN₂ O.1.2 C₇ H₈ O₃ S: C, 58.62; H, 6.72; N,6.10. Found: C, 58.62; H, 6.81; N, 6.45.

Example 1126-Fluoro-3-(1-(1,1-dimethylpropyl)-2-(R)-azetidinylmethoxy)pyridinetosylate

Following the procedures of Example 111a and b, except replacing the5-(2S)-azetidinylmethyloxy)-2-fluoropyridine thereof with5-(2R)-azetidinylmethyloxy)-2-fluoropyridine,5-[1-(1,1-dimethyl-2-propynyl)-(2R)-azetidinylmethoxy]-2-fluoropyridinewas prepared in 21% yield. Following the procedures of Example 111c andd, replacing5-[1-(1,1-dimethyl-2-propynyl)-(2S)-azetidinylmethoxy]-2-fluoropyridinethereof with the enantiomeric material5-[1-(1,1-dimethyl-2-propynyl)-(2R)-azetidinylmethoxy]-2-fluoropyridine,the title compound was prepared as a white solid: mp 67-70° C.; ¹ H NMR(D₂ O) δ 0.95 (t, J=7.3 Hz, 3H), 1.31 (s, 3H), 1.37 (s, 3H), 1.67 (m,2H), 2.40 (s, 3H), 2.54 (q, J=8.5 Hz, 1H), 4.02 (m, 1H), 4.15 (m, 1H),4.43 (m, 2H), 4.96 (m, 1H), 7.11 (dd, J=3.0, 9.2 Hz, 1H), 7.38 (d, J=8.5Hz, 2H), 7.67 (m, 1H), 7.70 (d, J=7.9 Hz, 2H), 7.92 (dd, J=1.8, 3.1 Hz,1H); MS (CI/NH₃) m/z 253 (M +H⁺); Anal. Calcd for C₁₄ H₂₁ FN₂ O.C₇ H₈ O₃S.0.8 H₂ O: C, 57.46; H, 7.03; N, 6.38. Found: C, 57.46; H, 6.95; N,6.27.

Example 1136-Difluoromethyl-3-((1-methyl-2-(S)-azetidinyl)methoxy)pyridine citrate

113a.6-Hydroxymethyl-3-((1-t-butoxycarbonyl-2-(S)-azetidinyl)methoxy)pyridine

A sample of (S)-1-t-butoxycarbonyl-2-azetidinemethanol (1.64 g, 8.18mmol) and 1.05 g (6.29 mmol) of 6-acetyloxymethyl-3-hydroxypyridine,prepared as described by Deady and Dayhe, Aust. J. Chem., 2565:36(1983), were reacted with triphenylphosphine (540 mg, 2.06 mmol) andDEAD (0.33 mL, 2.06 mmol) in TBF (25 mL) according to the procedure ofExample 2a. The product was stirred in methanol (4 mL) containing KOH(450 mg) at room temperature for 4 hours, then neutralized andconcentrated. The residue was purified by chromatography (silica gel;1:1 ether: hexane and ethyl acetate) to give title compound (240 mg, 41%for two steps). MS (DCI/NH₃) m/e: 295 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz)δ: 1.42 (s, 9H), 2.24-2.48 (m, 2H), 3.84-3.96 (m, 2H), 4.18 (dd, J=2.6,11 Hz, 1H), 4.40 (m, 1H), 4.53 (m, 1H), 4.82 (s, 2H), 7.36 (d, J=8.5 Hz,1H), 7.51 (m 1H), 8.31 (d, J=3.0 Hz, 1H).

113b.6-Difluoromethyl-3-((1-t-butoxycarbonyl-2-(S)-azetidinyl)methoxy)pyridine

To a sample of the compound of step 113a above (127 mg, 0.43 mmol) inphosphoric acid (3 mL) was added dicyclohexylcarbodiimide (310 mg, 1.5mmol), and the solution was stirred at 25° C. for 2 hours. The solid wasfiltered and the filtrate was then washed with saturated NaHCO₃. Theorganic layer was dried (MgSO₄), filtered, and the solvent was removed.The residue (110 mg) was used for next reaction without furtherpurification. MS (DCI/NH₃) m/e: 293 (M+H)⁺. To the crude product (110mg, 0.38 mmol) in methylene chloride (3 mL) was added triethylamine (0.1mL), and the solution was cooled to -78° C. To this solution was addedDAST (42 μL, 0.39 mmol), then the solution was stirred at -78-0° C. for1.5 hours. The reaction mixture was warmed to room temperature, and thereaction was quenched by the addition of saturated NaHCO₃. The mixturewas extracted with chloroform, the solvent was removed, and the residuewas chromatographed (silica gel; EtOAc/hexane, 1:1) to give the titlecompound (52 mg, 44%). MS (DCI/NH₃) m/e: 315 (M+H)⁺. ¹ H NMR (CDCl₃, 300MHz) 8: 1.55 (s, 9H), 2.34 (s, 3H), 2.11-2.44 (m, 2H), 3.90 (t, J=7.8Hz, 2H), 4.17 (dd, J=2.9, 10 Hz, 1H), 4.36 (m, 1H), 4.53 (m, 1H), 6.62(t, J=55.5 Hz, 1H), 7.36 (dd, J=2.5, 8.6 Hz), 7.57 (d, J=8.5 Hz, 1H),8.36 (d, J=3.0 Hz, 1H).

113c. 6-Difluoromethyl-3-((1-methyl-2-(S)-azetidinyl)methoxy)pyridinecitrate

The compound obtained from step 113b above was treated withp-toluenesulfonic acid (64.6 mg, 0.34 mmol) in methylene chloride (3mL). The resultant mixture was refluxed for 6 hours. The solvent wasremoved under reduced pressure. The residue was triturated with etherseveral times to give a white very hygroscopic solid (102 mg). MS(CI/NH₃) m/e: 215 (M+H)⁺, 232 (M+NH₄)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ: 2.38(s, 3H), 2.69 (q, J=8.5 Hz, 2H), 4.03-4.11 (m, 2H), 4.45 (d, J=4.4 Hz,2H), 4.96)m, 1H), 6.79 (t, J=55.5 Hz, 1H), 7.35 (d, J=7.5 Hz, 2H), 7.60(dd, J=2.7, 8.5 Hz, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.72 (d, J=8.8 Hz, 1H),8.39 (d, J=3.0 Hz, 1H). Anal. Calcd for C₁₀ H₁₂ F₂ N₂ O.2.5 C₇ H₈ SO₃.2H₂ O: C, 48.52; H, 5.33; N, 4.12.Found: C, 48.46; H, 5.27 N, 4.10.[α]_(D) ²⁵ =1° (c0.28, MeOH).

Example 114 3-(2-(R)-Azetidinylmethoxy)-5-chloropyridine tosylate

114a. 3-(1-t-butoxycarbonyl-2-(R)-azetidinylmethoxy)-5-chloropyridine

To a solution of 5-chloro-3-hydroxypyridine (0.3 g, 2.6 mmol) in DMF wasadded KOH (0.2 g, 3.8 mnol) at room temperature.1-t-Butoxycarbonyl-2-(R)-azetidinylmethyl tosylate (0.8 g, 2.4 mmol,from example 10d) was then added, and the reaction mixture was stirredat 80° C. for 16 hours. The DMF was removed by washing with H₂ O/brine(1:1) in EtOAc. The organic layer was dried, concentrated andchromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil(0.6 g, 87%): ¹ H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 2.21-2.40 (m,2H), 3.89 (t, 2H, J=8 Hz), 4.12 (m, 1H), 4.36 (m, 1H), 4.52 (m, 1H),7.29 (m, 1H), 8.20 (d, 1H, J=2 Hz), 8.25 (d, 1H, J=3 Hz); MS (CI/NH₃)m/z 299 (M+H)⁺.

114b. 3-(2-(R)-Azetidinylmethoxy)-5-chloropyridine tosylate

To a solution of3-(1-t-butoxycarbonyl-2-(R)-azetidinylmethoxy)-5-chloropyridine (0.6 g,2.1 rnmol) in CH₂ Cl₂ (4 mL) was added TFA (3 mL) at 0° C. The reactionmixture was allowed to stir at 0° C.-25° C. After 30 minutes, it wasbasified with 15% NaOH and extracted with CH₂ Cl ₂. The organic solventwas dried (MgSO₄), concentrated and chromatographed (silica gel; CH₂ Cl₂/MeOH, 10:0.4 to 10:1) to afford an oil (0.4g, 93%): ¹ H NMR (CDCl₃, 300MHz) δ 2.44-2.64 (m, 2H), 3.80 (m, 1H), 3.98 (m, 1H), 4.08 (m, 1H), 4.24(m, 1H), 4.61 (m, 1H), 7.26 (m, 1H), 8.23 (m, 1H); MS (CI/NH₃) m/z 199(M+H)⁺. The free base was converted to the salt with TsOH. white solid:mp 100-102° C.; ¹ H NMR (D₂, 300 MHz) δ 2.38 (s, 3H), 2.60-2.78 (m, 2H),4.00-4.20 (m, 2H), 4.39-4.43 (m, 2H), 4.98 (m,1H), 7.36 (d, 2H, J=8 Hz),7.60 (m, 1H), 7.67 (d, 2H, J=8 Hz), 8.20-8.24 (m, 2H); MS (CI/NH₃) m/z199 (M+H)⁺. Anal. Calcd for C9H11ClN2O.TsOH.0.5 H₂ O: C, 50 59; H, 5.31;N, 7.37. Found: C, 50.91; H, 5.02; N, 7.00. [α]_(D) ²⁵ 9.3° (c 0.4,MeOH).

Example 115 6-Methyl-3-(2-(R)-azetidinylmethoxy)pyridine

The title compound was prepared by the procedure of example 17,substituting 1-t-butoxycarbonyl-2-(R)-azetidinemethanol for the (S)enantiomer therein, and substituting 6-methyl-3-pyridinol for the3-bromo-2-chloro-5-hydroxypyridine. After deprotection and conversion tothe HCl salt as in example 17a, a white solid was obtained: mp 134-136°C.; ¹ H NMR (D₂ O 300 MHz) δ 2.48 (s, 3H), 2.69 (m, 2H), 4.12 (m, 2H),4.41 (d, J=4 Hz, 2H), 4.95 (hept, J=4 Hz, 1H), 7.32 (d, J=9 Hz, 1H),7.47 (dd, J=3, 9 Hz, 1H), 8.20 (d, J=3 Hz, 1H); MS (DCI/NH₃) m/e 179(M+H)⁺. Anal. calcd. for C₁₀ H₁₄ N₂ O.HCl.H₂ O: C, 54.13; H, 7.18; N,12.62. Found: C, 53.85; H, 6.98; N, 12.38.

Example 116 2,6-Difluoro-3-(2-(S)-azetidinylmethoxy)pyridine tosylate

116a. 3-Hydroxy-2,6-difluoropyridine

To a solution of 2, 6-difluoropyridine (6.7 mL, 73.8 mmole) in THF (100mL, cooled to -78° C.) was added a 2M solution of LDA inheptane/THF/ethylbenene (38 mL, 76 mmol). The mixture was stirred at-78° C. for 1 hour, and trimethyl borate (6.8 mL, 89.7 mmol) was added.The mixture was stirred for 1 hour and allowed to warm to 20° C., thenthe reaction was quenched with HOAc (10 mL). The solution was made basicwith 20% aq NaOH (20 mL), H₂ O₂ (50%, 200 mL) was added, and the mixturestirred for 16 hours. The mixture was neutralized by addition of HCl(2M, aq) and extracted with EtOAc. The combined EtOAc extracts weredried (MgSO₄). The solvent was evaporated under vacuum, and the crudeproduct was chromatographed (silica gel; hexane/EtOAc 9:1 to 6:4) toyield 2.7g (28%) of the title compound. ¹ H NMR (DMSO-d₆, 300 MHz) δ:6.75 (dd, J=3.0, 5.5 Hz, 1H), 7.48 (m, 1H). MS (DCI/NH₃) m/e 149(M+NH₄)⁺.

116b. 2,6-diFluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine

2,6-DiFluoro-3-hydroxypyridine from Example 116a (2g, 15.26 mmole),1-Cbz-2-(S)-azetidinemethyl tosylate (5.73 g 15.26 mmole, prepared inexample 105), and KOH (1.4 g 24.9 mmole) were combined in DMF (15 mL)and heated at 90° C. for one hour, cooled to 20° C. and poured intobrine (100 mL). The resulting mixture was extracted with ether. Thecombined Et₂ O extracts were washed with 50% brine and dried (MgSO₄).The solvent was evaporated in vacuo and the crude product waschromatographed (silica gel; hexane/EtOAc 95:5 to 6:4) to yield 1.75g(34%) of the title compound. ¹ H NMR (DMSO-d₆, 120° C. 300 MHz) δ: 2.22(m, 1H), 2.42 (m, 1H), 3.85-3.90 (m, 2H), 4.23 (m, 1H), 4.40 (m, 1H),4.54 (m, 1H), 5.01 (s, 1H), 6.93 (dd, J=3.0, 5.5, 1H), 7.29 (m, 5H),7.77 (m, ¹ H).MS (DCI/NH₃) m/e 335 (M+H)⁺, 352 (M+NH₄)⁺. Anal. calcd.for C₁₇ H₁₆ F₂ N₂ O₃,: C 61.07 H, 54.82 N, 8.38 Found: C, 61.10 H, 4.84;N, 7.90.

116c. 2,6-diFluoro-3-(2-(S)-azetidinylmethoxy)pyridine tosylate

2,6-Difluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine from Example 116b(640 mg, 1.9 mmol) was combined with 10% Pd on C (50 mg) and ptoluenesulfonic acid monohydrate (1.1 g, 5.7 mmole) in 30 mL of EtOH,and the mixture was stirred under an H₂ atmosphere for 16 hours. Themixture was concentrated, triturated with ether and then recrystallizedfrom ethyl acetate/ether to yield 231 mg (32.4%) of the title compound:mp 140-143° C. ¹ H NMR (D₂ O 300 MHz) 6: 2.40 (s, 3H), 2.69 (m, 2H),4.12 (m, 2H), 4.46 (d, J=4.5, 2H), 4.94 (m, 1H), 7.01 (m, 1H), 7.38(d,J=8.0, 2H), 7.70 (d,J=8.0, 2H), 7.81 (m, 1H). MS (DCI/NH₃) m/e 201(M+H)⁺, 218 (M+NH₄)⁺. Anal. calcd. for C₉ H₁₀ F₂ N₂ O.C₇ H₈ O₃ S: C,51.61H, 4.87 N, 7.52 Found: C, 51.37 H, 4.89; N, 7.40. [α]_(D) -1.44 (c1, MeOH).

Example 117 2-Fluoro-6-methyl-3-(2-(S)-azetidinylmethoxy)pyridinetosylate

117a. 3-Hydroxy-6-methyl-2-nitropyridine

5-Hydroxy-2-methylpyridine (23.6 g, 216 mmole)was dissolved in conc. H₂SO₄ (50 mL) and cooled to 0° C. Fuming HNO₃ (50 mL) was added over onehour. The solution was stirred at room temperature for one hour, pouredonto ice (400 g), and filtered. The solids were dissolved in EtOAcwashed with brine (100 mL). The organic extracts were dried (MgSO₄), andthe solvent was evaporated to yield 12.1 g (36.3%) of the titlecompound. mp 102-105° C. ¹ H NMR (DMSO-d₆, 300 MHz) δ: 2.44 (s, 3H),7.52 (d, J=8.5 Hz, 1H), 7.58 (d J=8.5 Hz, 1H). MS (ESI -Q1MS) m/e153(M-H)⁺. Anal. calcd. for C₆ H₆ N₂ O₃ C, 46.76 H, 3.92; N, 18.18Found: C, 46.65 H, 3.98; N, 18.10.

117b. 2-Amino-3-hydroxy-6-methylpyridine

3-Hydroxy-6-methyl-2-nitropyridine from Example 117a (10.5 g, 68 mmole)was combined with 10% Pd/C (100 mg) in EtOH (100 mL), and the mixturewas stirred under a H₂ atmosphere for 16 hours. The mixture was filteredand concentrated to yield 8.40 g (99%) of the title compound. mp141-145° C. ¹ H NMR (DMSO-d₆, 300 MHz) δ: 2.14 (s, 3H), 6.22 (d, J=7.5Hz, 1H), 6.71 (d J=7.5 Hz, 1H). MS (DCI/NH₃) m/e 125 (M+H)⁺, 142(M+NH₄)⁺.

117c. 2-Fluoro-3-hydroxy-6-methylpyridine

2-Amino-3-hydroxy-6-methylpyridine from Example 117b (8.35 g, 67.25mmol) was dissolved in aquious HF (48% 100 mL) and cooled to -5° C.NaNO₂ (5.2 g, 75.4 mmol) was added at a rate that maintained thetemperature below 0° C. After the addition was complete, the solutionwas heated to 30° C. After 30 minutes, the solution was cooled to 0° C.,and the solution was neutralized by addition of NaOH (20% aq) Theaqueous mixture was extracted with ethyl acetate. The organic extractswere dried (MgSO₄), and the solvent was evaporated. The crude productwas chromatographed (silica gel; hexane/EtOAc 1:1) to yield 4.68g(54.7%) of the title compound. mp 133-135° C. ¹ H NMR (DMSO-d₆, 300 MHz)δ: 2.29 (s, 3H), 6.98 (d, J=8 Hz, 1H), 7.26 (dd J=8 Hz, 1H). MS(DCI/NH₃) m/e 128 (M+H)⁺, 145 (M+NH₄)⁺. Anal. calcd. for C₆ H₆ FNO C,56.69; H, 4.76 N, 11.02. Found: C, 56.72; H, 4.73; N, 11.03.

117d. 2-Fluoro-6-methyl-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine

2-Fluoro-3-hydroxy-6-methylpyridine from Example 117c (1 g 7.87 mmole),1-Cbz-2-(S)-azetidinemethyl tosylate (2.37 g 7.5 mmole, prepared as forexample 105) and KOH (0.66 g 11.76 mmole) were combined in DMF (25 mL)and heated at 90° C. for one hour, cooled to 20° C. and poured intobrine (100 mL). The resulting mixture was extracted with ether. Thecombined Et₂ O extracts were washed with 50% brine and dried (MgSO₄).The solvent was evaporated under vacuum, and the crude product waschromatographed (silica gel; hexane/EtOAc 3:1) to yield 1.31 g (53%) ofthe title compound. ¹ H NMR (DMSO-d₆, 120° C. 300 MHz) δ: 2.26 (m, 1H),2.33 (s, 3H), 2.48 (m, 1H), 3.82-3.88 (m, 2H), 4.19 (q, J=3, 1H), 4.35(q, J=4.5, 1H), 4.53 (m, 1H), 5.01 (s, 211), 7.01 (d, J=8, 1H), 7.28 (m,5H), 7.43 (m, 1H). MS (DCI/NH₃) m/e 331 (M+H)⁺, 348 (M+NH₄)⁺. Anal.calcd. for C₁₈ H₁₉ FN₂ O₃ C, 65.44; H, 5.8; N, 8.48. Found: C, 65.04 H,5.86; N, 8.44; [α]_(D) -70.38 (c 1, MeOH).

117e. 2-Fluoro-6-methyl-3-(2-(S)-azetidinylmethoxy)pyridine tosylate

2-Fluoro-6-methyl-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine from Example117d (714 mg, 2.16 mmol) was combined with 10% Pd/C (50 mg) andp-toluenesulfonic acid monohydrate (830 mg, 4.36 mmole) in 30 mL ofEtOH, and the mixture was stirred under an H₂ atmosphere for 16 hours.The mixture was filtered, concentrated, the residue was triturated withether, and the product was recrystallized from ethyl acetate/ether toyield 480 mg (60%) of the title compound. mp 141-143° C. ¹ H NMR (D₂ O300 MHz) δ: 2.40 (s, 6H), 2.65-2.71 (m, 2H), 4.07-4.16 (m, 2H), 4.43(d,J=4.5, 2H), 4.81-95 (m, 1H), 7.16 (d, J=8.0, 1H), 7.37 (d,J=8.0, 2H),7.55 (dd, J=8.0, 2.5, 1H), 7.70 (d,J=8.0, 2H). MS (DCI/NH₃) m/e 197(M+H)⁺ 214 (M+NH₄)⁺. Anal. calcd. for C₁₀ H₁₃ FN₂ O.C₇ H₈ O₃ S: C, 55.42H, 5.75 N, 7.60. Found: C, 55.27 H, 5.69; N, 7.44. [α]_(D) -3.2 (c 1,MeOH).

Example 118 2-Fluoro-6-methyl-3-(2-(R)-azetidinylmethoxy)pyridinetosylate

118a. 2-Fluoro-6-methyl-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine

2-Fluoro-3-hydroxy-6-methylpyridine from Example 117c (0.5 g 3.47mmole), 1-Cbz-2-(R)-azetidinemethyl tosylate (1.1 g 3.9 mmole) fromexample 98a and KOH (0.3 g 5.33 mmole) were combined in DMF (5 mL) andheated at 80° C. for two hours, cooled to rt and poured into saturatedNH₄ Cl (100 mL). The resulting mixture was extracted with ether, and thecombined Et₂ O extracts were washed with 50% brine and dried (MgSO₄).The solvent was evaporated under vacuum, and the crude product waschromatographed (silica gel; hexane/EtOAc 9:1 to 7:3) to yield 592 mg(51.7%) of the title compound. ¹ H NMR (DMSO-d₆, 120° C. 300 MHz) δ 2.22(m, 1H), 2.33 (s, 3H), 2.41 (m, 1H), 3.83-3.88 (m, 2H), 4.19 (q, J=3,1H), 4.35 (q, J=5, 1H), 4.53 (m, 1H), 5.01 (s, 2H), 7.01 (d, J=8, 1H),7.28 (m, 5H), 7.43 (m, 1H). MS (CI/NH₃) m/e 331 (M+H)⁺ 348 (M+NH₄)⁺.Anal. calcd. for C₁₈ H₁₉ FN₂ O₃ C, 65.44; H, 5.8; N, 8.48. Found: C,65.19 H, 5.95; N, 8.69; [α]_(D) +68.15 (c 1, MeOH).

118b. 2-Fluoro-6-methyl-3-(2-(R)-azetidinylmethoxy)pyridine tosylate

2-Fluoro-6-methyl-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine from step118a (500 mg, 1.51 mmol) was combined with 10% Pd/C (50 mg) and ptoluenesulfonic acid monohydrate (600 mg, 3.15 mmole) in 30 mL of EtOH,and the mixture was stirred under an H₂ atmosphere for 16 hours. Themixture was filtered, concentrated, the residue was triturated withether, and the product was recrystallized from ethyl acetate/ether toyield 270 mg (50%) of the title compound. mp 158-160° C. ¹ H NMR (D₂ O300 MHz) δ 2.40 (s, 6H), 2.65-2.70 (m, 2H), 4.07-4.18 (m, 2H), 4.42 (d,J=4.5, 2H), 4.91-95 (m, 1H), 7.15 (d, J=8.0, 1H), 7.37 (d,J=8.0, 2H),7.55 (dd, J=8.0, 2.0, 1H), 7.69 (d,J=8.5, 2H). MS (DCI/NH₃) m/e 197(M+H)⁺ 214 (M+NH₄)⁺. Anal. calcd. for C₁₀ H₁₃ FN₂ O.C₇ H₈ O₃ S.0.4 H₂ O:C, 54.36 H, 5.85 N, 7.46. Found: C, 54.48 H, 5.81; N, 7.28; [α]_(D)+2.05 (c 1, MeOH).

Example 119 6-Methoxy-3-(2(R)-azetidinylmethoxy)pyridine

119a. 5-acetoxy-2-methoxypyridine

To 47.6 mL of boron trifluoride etherate (387 mmol, Aldrich) cooled to-10° C. under N2 was added 24 g (193mmol, Aldrich)) of5-amino-2-methoxypyridine dissolved in 100 mL of dimethoxyethane. Thentert-butyl nitrite (20.2 mL, 193 mmol, Aldrich) was added at a ratewhich kept the temperature below 0° C. After 1 hour at -10° C. pentane(400 mL) was then added to the reaction mixture, the pentane solutionwas decanted, and the residue was washed with cold ether and dissolvedin 200 mL of acetic anhydride. The resulting solution was heated to 100°C.±5° C. for 1 hour. The solvent was removed under vacuum, and theresidue was suspended in saturated aqueous Na₂ CO₃ (200 mL) andextracted with ethyl ether (3×200 mL). The ether solution was dried(MgSO₄), the solvent was removed in vacuo, and the residue waschromatographed on silica gel, eluting with 95:5 to 80:20 hexane:ethylacetate to give 7.3 (20.7%) g of the title compound. MS (CI/NH₃) m/e:168 (M+H)⁺, 185 (M+NH₄)+. ¹ H NMR (CDCl₃ 300 MHz) δ 2.30 (s, 3H), 3.92(s, 3H), 6.75 (d, J=9.0 Hz 1H), 7.35 (dd, J=2.5,9.0 1H), 7.95 (d, J=3.0Hz 1H). Anal. calcd. for C₈ H₉ NO₃ C, 57.48 H, 5.43; N, 8.38. Found: C,57.46 H, 5.40; N, 7.99.

119b. 2-methoxy-5-hydroxypyridine

The product of Example 119a (6.8 g, 40.7 mmol) was dissolved in 20%aqueous NaOH (50 mL) at 0° C., and the solution was warmed to roomtemperature and stirred for 3 hours. The solution was neutralized byaddition of HCl, and the aqueous mixture was extracted with ethylacetate. The organic extracts were washed with water and brine, thendried (MgSO₄), and the solvent was evaporated to yield 5.05 g (99%). Theproduct was recrystalized from ethyl acetate/hexane to yield 3.6 g(70.6%) of the title compound. mp 80-82° C.; MS m/e: 126 (M+H)⁺ ; 143(M+NH₄)⁺. ¹ H NMR (CDCl₃, 300 MHz) 67 3.88 (s, 3H), 6.69 (d, 1H, J=9.0Hz), 7.23 (dd, 1H, J=3.0, 9.0 Hz), 7.78 (d, 1H, J=3.0 Hz). Anal. calcd.for C₆ H₇ NO C, 57.59 H, 5.64; N, 11.19. Found: C, 57.55 H, 5.62; N,11.13.

119c. 6-methoxy-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine

3-Hydroxy-6-methoxypyridine from Example 119b (514 mg, 4.1 mmole),1-Cbz-2-(R)-azetidinemethyl tosylate (1.2 g, 3.26 mmole) from Example98a and KOH (335 mg 6 mmole) were combined in DMF (10 mL) and heated at80° C. for 3 hours, cooled to rt and poured into Na₂ CO₃ (100 mL). Theresulting mixture was extracted with ether, and the combined Et₂ Oextracts were washed with 50% brine and dried (MgSO₄). The solvent wasevaporated under vacuum, and the crude product was chromatographed(silica gel; hexane/EtOAc, 9:1 to 7:3) to yield 672 mg (67.2%) of thetitle compound. ¹ H NMR (DMSO-d₆, 120° C. 300 MHz) δ 2.20 (m, 1H), 2.37(m, 1H), 2.82 (s, 3H), 3.82-3.88 (m, 2H), 4.13 (m, 1H), 4.27 (m, 1H),4.52 (m, 1H), 5.02 (s, 1H), 6.67 (d, J=11, 1H), 7.26-7.32 (m, 6H), 7.83(d,J=3, 1H). MS (DCI/NH₃) m/e 331 (M+H)⁺, 348 (M+NH₄)⁺. Anal. calcd. forC₁₈ H₂₀ N₂ O₄ C, 65.84; H, 6.14; N, 8.53. Found: C, 65.98 H, 6.23; N,8.51.

119d. 6-methoxy-3-(2-(R)-azetidinylmethoxy)pyridine

6-methoxy-3-(1-Cbz-2-(R)-azetidinylmethoxy)pyridine from Example 119c(300 mg, 0.91 mmol) was combined with 10% Pd/C (50 mg) in 30 mL of EtOH,and the mixture was stirred under an H₂ atmosphere for 16 hours. Themixture was filtered and concentrated. The crude free base was convertedto the salt by treatment with p toluenesulfonic acid in ethyl acetate.The mixture was concentrated, the residue was triturated with ether, andthe product was recrystalized from ethyl acetate/ether to give 167 mg(33.9%) of the title compound: mp 139-142° C.; ¹ H NMR (D₂ O 300 MHz) δ2.39 (s, 6H), 2.60-2.70 (m, 2H), 2.98 (s, 3H), 4.04-4.15 (m, 2H), 4.36(d, J=4.5, 2H), 4.95 (s, 1H), 7.08 (d, J=9.0, 1H), 7.36 (d, J=8.0, 4H),7.68 (d, J=8.0, 4H), 7.75 (dd, J=3.5, 9.5, 1H), 7.91 (d, J=3.0, 1H); MS(DCI/NH₃) m/e 195 (M+H)⁺. Anal. calcd. for C₁₀ H₁₄ N₂ O₂.2C₇ H₈ O₃ S: C,53.52 H, 5.61N, 5.20. Found: C, 53.24 H, 5.68; N, 5.07. [α]_(D) +3.55(c1, MeOH).

Example 120 5-Ethoxy-3-(2-(S)-azetidinylmethoxy)pyridine tosylate

120a. 3-Benzyloxy-5-bromopyridine

NaH (60% in mineral oil) (40.9 g, 1.03 mol) in 800 mL of DMF was cooledto 0° C. and benzyl alcohol (105 mL, 1.02 mol) was added slowly. Thereaction mixture was stirred for 1 hour at 20° C., then3,5-dibromopyridine (200.4 g, 846 mmol) was added and the mixture wasstirred for 16 hours. The mixture was quenched with saturated NH₄ Cl(500 mL), diluted with 400 mL of water and extracted with Et₂ O. Thecombined Et₂ O extracts were washed with 50% brine and dried (MgSO₄).The solvent was evaporated under vacuum, and the crude product wasrecrystallized from Et₂ O to afford 161 g (72%) of the title product: mp63-68° C.; ¹ H NMR (CDCl₃, 300 MHz) δ 5.1 (s, 1H), 7.35-7.50 (m, 6H),8.27-8.37 (m, 2H); MS (CI/NH₃) m/z: 264, 266 (M+H)⁺.

120b. 3-Amino-5-benzyloxypyridine

The product of step 120a (41.3 g, 156 mmol), copper (I) bromide (22.43g, 156 mmol), MeOH (275 mL), and liquid NH₃ (50 mL) were combined in astainless steel reactor and heated to 130° C. for 24 hours. The mixturewas allowed to cool to ambient temperature, then concentrated. Theresidue was suspended in 300 mL of saturated aqueous Na₂ CO₃ andextracted with CH₂ Cl₂. The combined CH₂ Cl₂ extracts were washed withbrine, dried (MgSO₄), and concentrated. The crude product waschromatographed (silica gel; hexane/EtOAc, 9:1 to 7:3) to afford 15.6 g(50%) of the title compound: ¹ H NMR (CDCl₃, 300 MHz) δ 5.10 (s, 2H),7.30-7.45 (m, 6H), 8.20-8.30 (m, 2H); MS (CI/NH₃) m/z: 201 (M+H)⁺.

120c. 3-Acetoxy-5-benzyloxypyridine

To boron trifluoride etherate (9.3 mL, 75 mmol) cooled to -15° C. underN₂ was added the product of Step 120b (10 g, 50 mmol) dissolved in DME(100 mL). Ten-butyl nitrite (7.8 mL, 65 mmol) was added at a rate whichkept the temperature below -5° C. After 10 minutes at -10° C., thereaction was warmed to 5° C. and stirred for 30 min. Pentane (200 mL)was then added to the reaction mixture, and the solid was collected bysuction filtration, washed with cold Et₂ O, and dissolved in aceticanhydride (150 mL). The resulting solution was heated to 70° C. until N₂envolution stopped. The solvent was removed under vacuum, and theresidue was suspended in saturated aqueous Na₂ CO₃ (150 mL) andextracted with Et₂ O. The Et₂ O extract was dried (Na₂ SO₄) andconcentrated. The crude product was chromatographed (silica gel;hexane/EtOAc, 6:1) to yield 2.0 g of the title compound: ¹ H NMR (CDCl₃,300 MHz) δ 2.35 (s, 3H), 5.15 (s, 2H), 7.15 (t, 1H, J=3 Hz), 7.35-7.42(m, 5H), 8.15 (d, 1H, J=3 Hz), 8.30 (d, 1H, J=3 Hz); MS (CI/NH₃) m/z:244 (M+H)⁺, 261 (M+NH₄)⁺.

120d. 3-Benzyloxy-5-hydroxypyridine

The product of Step 120c (2 g, 8.4 mmol) was dissolved in methanol (15mL), and K₂ CO₃ (600 mg, 4.34 mmol) was added. After consumption of thestarting material, the solution was neutralized by addition of aqueous1N HCl. The mixture was extracted with Et₂ O, and the organic extractswere dried (Na₂ SO₄) and concentrated. The crude product was trituratedwith hexane to provide the title compound (1.3 g, 82%) as white solid: ¹H NMR (DMSO, 300 MHz) δ 5.15 (s, 2H), 6.80 (t, 1H, J=3 Hz), 7.35-7.42(m, 5H), 7.75 (d, 1H, J=3 Hz), 7.85 (d, 1H, J=3 Hz), 9.95 (br s, 1H); MS(CI/NH₃) m/z: 202 (M+H)⁺, 219 (M+NH₄)⁺.

120e. 5-Benzyloxy-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine

1-Boc-2-(S)-azetidinylmethanol (36.5 g, 0.195 mol) was dissolved in 195mL of CH₂ Cl₂ followed by addition of triethylamine (35.6 ml, 0.255 mol)and toluenesulfonyl chloride (48.5 g, 0.254 mol). The resulting mixturewas stirred at room temperature for 16 hours. A 10% solution of NaOH wasadded rapidly, and the mixture was stirred for one hour. After phaseseparation, the aqueous phase was extracted with additional CH₂ Cl₂,combined with the organic phase, and then washed with NaHCO₃ solutionand brine. The resulting solution was dried (MgSO₄), filtered, andconcentrated under vacuum to give 63.1 g ofBoc-(S)-toluensulfonyloxymethylazetidine (94.8%).

Next, a solution of 3-benzyloxy-5-hydroxypyridine (350 mg, 1.74 mmol,from step 120d) in DMF (20 mL) was treated with ground KOH (154 mg, 2.74mmol) and stirred for 30 minutes at 80° C. To this mixture was rapidlyadded the Boc-(S)-toluensulfonyloxymethylazetidine (585 mg, 1.74 mmol)dissolved in DMF (5 mL), and the mixture was stirred for 16 hours at 80°C. The mixture was concentrated under vacuum to remove the DMF, and theresidue was diluted with water and extracted with EtOAc. The organicextracts were combined, dried (Na₂ SO₄), filtered, and concentratedunder vacuum to give 800 mg of crude product. This material was purifiedby chromatography (silica gel; hexane/EtOAc, 10:1) to give the titlecompound (575 mg, 90%): ¹ H NMR (CDCl₃, 300 MHz) δ 1.40 (s, 9H),2.26-2.30 (m, 2H), 3.90-2.94 (m, 2H), 4.16 (m, 1H), 4.35 (m, 1H), 4.54(m, 1H), 5.10 (s, 2H), 6.95 (s, 1H), 7.40-7.46 (m, 5H), 8.20 (br s,(2H): MS (CI/NH₃) m/z: 371 (M+H)⁺.

120f. 5-hydroxy-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine

The product of step 120e (5.0g, 13.51 mmol) in MeOH (25 mL) was stirredunder an atmosphere of H₂ in the presence of 10% Pd/C (200 mg) for 4hours. The mixture was filtered and concentrated to afford 3.4 g (92%)of the title compound as colorless oil: ¹ H NMR (CDCl ₃, 300 Hz) δ 1.40(s, 9H), 2.30 (m, 2H), 3.90 (t, J=9 Hz, 2H), 4.10 (m, 1H), 4.30 (m, 1H),4.50 (m, 1H), 6.85 (m, 1H), 7.85 (m, 1H), 7.95 (m, 1H). MS (CI/NH₃) 281(M+H)⁺.

120g. 5-Ethoxy-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine

A solution of 5-hydroxy-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine (500mg, 1.78 mmol, from step 120f) in dimethylformamide (15 mL) was treatedwith ground KOH (170 mg, 1.7 mmol) and stirred for 30 minutes at roomtemperature. To this mixture was rapidly added ethyl p-toluenesulfonate(430 mg, 2.14 mmol), and the resultant was stirred at 80° C. overnight.The mixture was concentrated to remove the dimethylformamide, and theresidue was diluted with water and extracted with EtOAc. The organicextracts were combined, dried (MgSO₄), filtered and concentrated undervacuum to give 1.0 g of unpurified product. This material was purifiedby chromatography (silica gel: hexane/EtOAc, 1:1) to give 537 mg (98%)of the title compound. ¹ H NMR (CDCl₃, 300 MHz) δ: 1.40 (s, 9H), 1.42(t, J=6 Hz, 3H), 2.30 (m, 2H), 3.92 (t, J=9 Hz, 2H), 4.05 (q, J=6 Hz,2H), 4.30 (m, ¹ H), 4.54 (m, 1H), 6.80 (m, 1H), 7.95 (m, 2H). MS(CI/NH₃) m/e: 309 (M+H)⁺.

120h. 5-Ethoxy-3-(2-(S)-azetidinylmethoxy)pyridine

To the 5-ethoxy-3-(2-(1-Boc-2-(S)-azetidinylmethoxy)pyridine from step120g (540 mg, 1.75 mmol) was added trifluoroacetic acid (1.5 mL) inmethylene chloride (15 mL) at 0° C. The solution was stirred for 2hours, allowed to warm to room temperature, then adjusted to pH 11 withaqueous 10% NaOH, and extracted with CH₂ Cl₂. The organic layer wasdried over MgSO₄ and concentrated. The residue was chromatographed(silica gel; CHCl₃ :MeOH, 95:5) to afford the free base of the titlecompound (300 mg, 82%). ¹ H NMR (CDCl₃, 300 MHz) δ: 1.42 (t, J=6 Hz,3H), 2.18 (m, 2H), 2.95 (m, 1H), 3.58 (m, 2H), 4.02 (m, 2H), 4.15 (q,J=6 Hz, 2H), 6.75 (t, J=3 Hz, 1H), 7.95 (t, J=3 Hz, 2H). MS (CI/NH₃)m/e: 209 (M+H)⁺.

120i. 5-Ethoxy-3-(2-(S)-azetidinylmethoxy)pyridine tosylate

The compound from step 120h (100 mg, 0.484 mmol) was converted to thesalt by treatment with p-toluenesulfonic acid in ethanol to give thetitle compound (125 mg): mp 105° C. (dec); [α]²⁵ _(D) =6.8° (c=0.47,MeOH); ¹ H NMR (CDCl₃, 300 MHz) δ 1.40 (t, J=6 Hz, 3H), 2.35 (s, 3H),2.50 (m, 2H), 3.95 (q, J=6 Hz, 2H), 4.15 (m, 2H), 4.38 (d, J=3 Hz, 2H),4.98 (br, 1H), 6.95 (t, J=3 Hz, 1H), 7.10 (d, J=6 Hz, 2H), 7.65 (d, J=6Hz, 2H), 7.90 (d, J=3 Hz, 1H), 8.02 (d, J=3 Hz, 1H); MS (CI/NH₃) m/z 209(M+H)⁺. Anal. calcd. for C₁₁ H₁₆ N₂ O₂.1.2 TsOH.0.8 H₂ O: C, 54.28; H,6.39 N, 6.53. Found: C, 54.60; H, 6.29; N, 6.20.

Example 121 2-Chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

121a. 2-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

To a solution of triphenylphosphine (1.73 g, 6.6 mmol) in THF (26 mL)was added diethyl azodicarboxylate (1.04 mL, 6.6 mmol) at 0° C., and thereaction mixture was stirred for 15 minutes.1-BOC-2-(S)-azetidinemethanol (1.03 g, 5.5 mmol) and2-chloro-3-pyridinol (785 mg, 6.0 mmol, Aldrich Chemical Co.) were thenadded. The reaction mixture was allowed to warm slowly to roomtemperature and stir overnight. Solvent was removed, and the residue wasdissolved in ethyl acetate. The solution was washed with saturatedaqueous K₂ CO₃ and brine, dried over MgSO₄ and concentrated. The residuewas chromatographed on a silica gel column, eluting with ethylacetate:hexane (1:4 to 1:1) to afford the title compound (611 mg). MS(DCI/NH₃) m/z 299 (M+H)⁺.

121b. 2-chloro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

To 2-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 121a(469 mg, 1.66 mmol) was added TFA (5 mL) in methylene chloride (5 mL) at0° C., and the mixture was stirred for 30 minutes. The volatilecomponents were then removed under vacuum. The residue was treated withsaturated K₂ CO₃ solution, then extracted with methylene chloride, whichwas dried over MgSO₄ and concentrated. The residue was chromatographedon a silica gel column, eluting with chloroform:methanol:NH₄ OH(10:1:0-10:1:0.5) to afford the free base of the title compound (217mg). The base (156 mg) was dissolved in methylene chloride (3 mL) andthen converted to the salt by treatment with saturated HCl in ether togive the title compound (142 mg). mp 155-156° C. MS (DCI/NH₃) m/z 199,201 (M+H)⁺, 216 (M+NH₄)⁺. ¹ H NMR (D₂ O, 300 MHz) δ 2.7-2.79 (m, 2H),4.13-4.24 (m, 2H), 4.44-4.58 (m, 2H), 4.98 (m, 1H), 7.45 (dd, J=4.8, 8.1Hz, 1H), 7.59 (dd, J=1.5, 8.2 Hz, 1H), 8.03 (dd, J=1.4, 4.5 Hz, 1H).Anal. Calcd. for C₉ H₁₁ N₂ OCl.1.0 HCl: C, 45.98; H, 5.14; N, 11.91.Found: C, 45.76; H, 5.09; N, 11.64.

Example 122 2-Fluoro-3-(2(S)-azetidinylmethoxy)pyridine hydrochloride

122a. 2-Fluoro-3-hydroxypyridine

2-Amino-3-hydroxypyridine (8.25 g, 75 mmol; from Aldrich) was dissolvedin hydrogen fluoride-pyridine (100 g, Aldrich) and cooled to 0° C. Thensodium nitrite (5.4 g 78 mmol) was added over 30 min. The solution wasstirred for an additional 30 minutes and then slowly poured into 300 mLof 25% NaOH at 0° C. The aqueous mixture was filtered and then extractedwith CH₂ Cl₂ (6×75 nL). The aqueous solution was adjusted to pH 6 with20% aq NaOH and extracted with EtOAc (6×100 nL), then the combined EtOAcextracts were dried over MgSO₄ and concentrated. The residue waschromatographed (silica gel; hexane/EtOAc, 9:1 to 6:4) to afford 3.93 gof the title compound ¹ H NMR (CDCl₃, 300 MHz) δ 7.75(m, 1H), 7.37 (m,1H ), 7.11 (m, 1H). MS (DCI/NH₃) m/z 114 (M+H)⁺, 131 (M+NH₄)⁺.

122b. 2-Fluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine

The procedure of example 17a was followed, substituting2-fluoro-3-hydroxypyridine and 1-Cbz-2-(S)-azetidinemethanol for5-bromo-9-chloropyridine-3-ol and 1-BOC-2-(S)-azetidinemethanol,respectively. Yield: 56%. ¹ H NMR (DMSO-d₆, 130° C., 300 MHz): δ 7.72(m, 1H), 7.55 (m, 1H), 7.30-7.20 (m, 5H), 7.17 (m, 1H), 5.01 (s, 1H),4.56 (m, 1H), 4.41 (dd, J=11.11, 1H), 4.5 (dd, J=10.68, 1H), 3.90-3.85(t, J=7.26, 2H), 2.42 (m, 1H), 2.25 (m, 1H). MS (DCI/NH₃) m/z 334(M+H)⁺, 317 (M+NH₄)⁺.

122c. 2-Fluoro-3-(2-azetidinylmethoxy)pyridine hydrochloride

2-Fluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine (step 122b, 1.1 g,34.8 mmol) was combined with 100 mg of 5% Pd/C in EtOH (25 mL) and themixture was stirred under an H₂ atmosphere for 16 hours. The mixture wasfiltered and concentrated, and the crude product was chromatographed(silica gel; CHCl₃, 99:1 to 94:6) to afford 480 mg (76%) of the freebase. The base was converted to the salt by treatment with IM hydrogenchloride in ether. The salt was recrystallized three times fromEtOH/EtOAc/Et₂ O to give 150 mg of the title compound ¹ H NMR (D₂ O 300MHz) 67.81 (m. 1H), 7.67 (m, 1H), 7.35 (m, 1H), 4.97 (m, 1H), 4.5-4.48(t, J=2.04 Hz, 2H), 4.21-4.06 (m, 2H), 2.75-2.66 (tt, J=6.95 Hz, 2H). MS(DCI/NH₃) m/z 183 (M+H)⁺, 200 (M+NH₄)⁺ Anal. Calcd. for C₉ H₁₁ N₂OFeHCl.0.3 H₂ O: C, 48.24; H, 5.67; N, 12.50. Found: C,48.30: H, 5.56;N, 12.15.

Example 123 6-Cyano-3-(2(S)-azetidinylmethoxy)pyridine hydrochloride

123a. 3-amino-6-bromopyridine

A mixture of 2-bromo-5-nitropyridine (30.75 g, 151.5 mmol), water (250mL), and acetic acid (110 mL) was heated to 45° C. Iron powder (24.5 g,439 mmol) was added at a rate which kept the temperature below 53° C.,then the mixture was stirred at 48° C.±5° C. for one hour. The mixturewas cooled to room temperature and filtered through diatomaceous earthfilter aid, washing with ethyl acetate. The layers were separated andthe aqueous phase was extracted with ethyl acetate. The combined organicfractions were washed with saturated Na₂ CO₃ and brine, dried overMgSO₄, and the solvent was removed in vacuo. The residue waschromatographed (silica gel, hexane:EtOAc, 100:0 to 50:50) to give 20.4g of the title compound: MS (CI/NH₃) m/e: 173 (M+H)⁺, 190 (M+NH₄)⁺ ; ¹ HNMR (CDCl₃ 300 MHz) δ 6.86-6.90 (dd, 1H, J=8.5, 2.4 Hz) 7.21-7.23 (d,1H, J=8.2 Hz) 7.85-7.86 (d, 1H, J=3 Hz).

123b. 3-acetoxy-6-bromopyridine

To 25.6 mL of boron trifluoride etherate (208 mmol, Aldrich) cooled to-15° C. under N₂ was added 18 g (104 mmol) of 3-amino-6-bromopyridine(from Step 123a above) dissolved in 35 mL of dimethoxyethane. Thent-Butyl nitrite (14.7 mL, 125 mmol, Aldrich) was added at a rate whichkept the temperature below 0° C. Dimethoxyethane (65 mL) and methylenechloride (60 mL) were then added to aid stirring. After 10 minutes at-10° C. the mixture was allowed to warm to 5° C. and stirred for 30minutes. Pentane (400 mL) was then added to the reaction mixture, thesolid was collected by suction filtration, washed with cold ether, airdried, and dissolved in 125 mL of acetic anhydride. The resultingsolution was heated to 100° C.±5° C. for 1 hour. The solvent was removedin vacuo, and the residue was suspended in saturated aqueous Na₂ CO₃,and extracted with ethyl ether. The ether solution was dried over MgSO₄,the solvent was removed in vacuo, and the residue was chromatographed onsilica gel, eluting with 100:0 to 60:40 hexane:ethyl acetate to give13.6 g of the title compound: ¹ H NMR (CDCl₃ 300 MHz) δ 8.20 (m,1H).7.51 (d, J=8.5 Hz 1H),7.38 (dd, J=2.9, 7.5 Hz, 1H), 2.35 (s, 3H). MS(CI/NH₃) m/e: 216 (M+H)⁺, 233 (M+NH₄)⁺.

123c. 2-Bromo-5-hydroxypyridine

The product of Example 123b (12.8 g, 60 mmol was dissolved in 15%aqueous NaOH (50 mL) at 0° C., and the solution was allowed to warm toroom temperature and stirred for 60 minutes. After complete consumptionof the starting material the solution was neutralized by addition ofHCl. The aqueous mixture was extracted with ethyl acetate. The organicextracts were washed with water and brine, then dried (MgSO₄), and thesolvent was evaporated to yield 9.8 g of the title compound: ¹ H NMR(CDCl₃, 300 MHz) δ 7.12-7.16 (dd, 1H, J=3.2 Hz),7.36-7.39 (d, 1H, J=8.5Hz), 8.04-8.05 (d, 1H, J=2.4 Hz). MS m/e: 174 (M+H)⁺.

123d. 6-Bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

The product of Example 123c was coupled to 1-BOC-2-(S)-azetidinemethanolusing the procedure described in Example 17a. ¹ H NMR (CDCl₃, 300 MHz):1.42 (s, 9H), 2.20-2.43 (m, 2H), 4.88 (t, J=8.0 Hz, 2H), 4.17 (dd,J=3.0, 9.0 Hz, 1H), 4.30-4.39 (m, 1H), 4.434.58 (m,1H), 7.42 (t, J=2.0Hz, 1H), 8.25-8.32 (m, 2H). MS (DCI/NH₃) m/e: 343 (M+H)⁺, 360 (M+NH₄)⁺.

123e. 6-Cyano-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

To the product of Example 123d (1.22 g, 3.60 mmol) in degassed DMF (10mL) were added zinc cyanide (0.295 g, 2.50 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.249 g, 0.20 mmol) and themixture was heated at 80° C. for 5 hours. The mixture was cooled to roomtemperature and poured into saturated sodium bicarbonate. The aqueouslayer was extracted with EtOAc (400 mL), dried (MgSO₄) and concentratedin vacuo. The crude product was chromatographed (silica gel;EtOAc/hexane 1/1) to afford a colorless oil (0.784 g, 75%): ¹ H NMR(CDCl₃, 300 MHz) δ 1.42 (s, 9H), 2.22-2.42 (m, 2H), 3.82-3.87 (m, 2H),3.18 (dd, J=3.0, 9.0 Hz, 1H), 4.38-4.45 (m, 1H), 4.48-4.60 (m, 1H),7.32-7.58 (m, 1H), 7.62 (d, J=11.5 Hz, 1H), 8.42 (d, J=4.0 Hz, 1H). MS(DCI/NH₃) m/e: 290 (M+H)⁺, 307 (M+NH₄)⁺.

123f. 6-Cyano-3-(2(S)-azetidinylmethoxy)pyridine hydrochloride

The product of Example 123e was deprotected and converted to thehydrochloride salt according to the procedure described in Example 17b:¹ H NMR (CDCl₃) δ 2.66-2.74 (m, 2H), 4.02-4.19 (m, 2H), 4.50 (d, 2H,J=4.4 Hz), 4.84-4.99 (m, 1H), 7.63 (dd, 1H, J=3.0, 11.5 Hz), 7.97 (d,1H, J=8.8 Hz), 8.48 (d, 1H, J=3.0 Hz). MS (CI/NH₃): m/z 190.00 (M+H⁺),207.00 (M+NH₄ ⁺); Anal. Calcd. for C₁₀ H₁₁ N₃ O.1.0 HCl.0.1 Et₂ O.0.1 H₂O: C, 53.18; H, 5.66; N, 17.89. Found: C, 53.07; H, 5.46; N, 17.87.

Example 124 3-(2-(R)-azetidinylmethoxy)-5-bromo-6-methylpyridinetosylate

124a. 5-Bromo-6-methyl-3-(1-BOC-2-(R)-azetidinylmethoxy)pyridine

A mixture of 5-bromo-3-hydroxy-6-methylpyridine (1.10 g, 5.85 mmol) andKOH (0.52 g, 9.28 mmol) in DMF (20 mL) was heated at 80° C. for 1 h, anda solution of 1-BOC-2-(R)-toluenesulfonyloxymethylazetidine (2.0 g, 5.86mmol) in DMF (10 mL) was added. The reaction mixture was heated at 80°C. overnight. After cooling to room temperature, the brown solution wasdiluted with EtOAc (150 mL), washed with distilled water and brine,dried (Na₂ SO₄), and concentrated under vacuum. The crude product waschromatographed (silica gel; 1:1 EtOAc:hexane) to afford a colorless oil(1.18 g, 56%): ¹ H NMR (CDCl₃, 300 MHz) δ 1.43 (s, 9H), 2.30 (m, 2H),2.59 (s, 3H), 3.88 (t, 2H, J=7.5 Hz), 4.10 (dd, 1H, J=7.2 Hz), 4.29 (m,1H), 4.50 (m, 1H), 7.44 (d, 1H, J=2.7 Hz), 8.18 (d, 1H, J=2.7 Hz); MS(DCI/NH₃) m/z 357 (M)⁺.

124b. 3-(2-(R)-azetidinylmethoxy)-5-bromo-6-methylpyridine

A solution of the compound from Example 124a (0.5 g, 1.40 mmol) in CH₂Cl₂ (6 mL) was cooled to 0° C. with an ice-bath, and trifluoroacecticacid (3 mL) was added dropwise via a dropping addition funnel. Thereaction mixture was stirred at 0° C. for 2 hours. The mixture wasconcentrated under vacuum, and the resulting residue was taken up inEtOAc (40 mL) and washed with 1M aqueous K₂ CO₃. The basic aqueouswashes were combined, saturated with brine and back extracted severaltimes with EtOAc to recover the desired product. The combined organicextracts were dried (Na₂ SO₄) and concentrated under vacuum. The crudeproduct was chromatographed (silica gel; 80:19:1 CH₂ Cl₂ :MeOH:NH₄ OH)to afford a colorless oil (0.33g, 92%): ¹ H NMR (CDCl₃, 300 MHz) δ 2.30(m, 3H), 2.57 (s, 3H), 3.48 (m, 1H), 3.71 (q, 1H, J=8.0 Hz), 4.01 (m,2H), 4.28 (m, 1H), 7.41 (d, 1H, J=2.7 Hz), 8.15 (d, 1H, J=2.7 Hz); MS(DCI/NH₃), m/z 257 (M)⁺.

124c. 3-(2-(R)-azetidinylmethoxy)-5-bromo-6-methylpyridine tosylate

To a solution of 5-bromo-6-methyl-3-(2-(R)-azetidinylmethoxy)pyridine(0.32 g, 1.24 mmol) from Example 124b in EtOH (5 mL) was addedp-toluenesulfonic acid monohydrate (0.23 g, 1.21 mmol). The reactionmixture was stirred at rt for 30 min and concentrated under vacuum. Theresidue was taken up in MeOH (2 mL) and triturated with ether. Theprecipitate was collected by filtration and dried to give a white solid(0.48 g, 91%): mp 142-144° C.; [α]_(D) ²³ +5.2 (c 0.5, MeOH); ¹ H NMR(D₂ O, 300 MHz) δ 2.39 (s, 3H), 2.55 (s, 3H), 2.67 (q, 2H, J=8.5 Hz),4.09 (m, 2H), 4.37 (d, 2H, J=4.4 Hz), 4.92 (m, 1H), 7.35 (d, 2H, J=7.7Hz), 7.68 (d, 2H, J=8.5 Hz), 7.75 (d, 1H, J=2.8 Hz), 8.16 (d, 1H, J=2.7Hz); MS (DCI/NH₃) m/z 257 (M)⁺. Anal. Calcd for C₁₀ H₁₃ BrN₂ O.TsOH: C,47.56; H, 4.93; N, 5.62. Found: C, 47.42; H, 5.13; N, 6.59.

Example 125 5-bromo-6-fluoro-3-(2-(R)-azetidinylmethoxy)pyridine

The free base of the title compound was prepared according to theprocedures detailed in Example 31, replacing1-tert-butyloxy-(2S)-azetidinemethanol thereof with the enantiomericmaterial, 1-tert-butyloxy-(2R)-azetidinemethanol. The tosylate salt wasprepared by adding an equivalent of para-toluenesulfonic acidmonohydrate to an ethanolic solution of5-((2R)-azetidinylmethoxy)-3-bromo-2-fluoropyridine. The volatilecomponents were removed in vacuo and the residue was triturated with Et₂O then dried under vacuum to afford the title compound as a white solid:mp 238-240° C.; [α]_(D) ²¹ 8.4 (c 0.5, MeOH); ¹ H NMR (DMSO-d₆) δ 2.29(s, 3H), 2.39 (m, 1H), 2.52 (m, 1H), 3.93 (m, 2H), 4.36 (m, 1H), 4.43(m, 1H), 4.73 (m, 1H), 7.11 (d, 2H, J=7.9 Hz), 7.48 (d, 2H, J=7.9 Hz),8.00 (m, 1H), 8.08 (dd, 1H, J=2.4,4.9 Hz), 8.85 (br s, 2H); MS (CI/NH₃)m/z 261, 263 (M+H)⁺. Anal. Calcd for C₉ H₁₀ BrFN₂ O.1.7 TsOH.0.5 H₂ O:C, 44.17; H, 4.44; N, 5.10. Found: C, 44.07; H, 4.08; N, 4.70.

Example 126 5-ethyl-6-fluoro-3-(2-(S)-azetidinylmethoxy

126a. 3-Bromo-2-fluoro-5-nitropyridine

3-Bromo-2-chloro-5-nitropyridine (119 g, 0.500 mol, prepared accordingto V. Koch and S. Schnatterer, Synthesis, 1990, 497-498), potassiumfluoride (79.5 g, 1.37 mol), and tetraphenylphosphonium bromide (109 g,0.260 mol) were combined in acetonitrile (1.5 L) and heated at refluxfor 4 days until GLC indicated complete consumption of the3-bromo-2-chloro-5-nitropyridine. The volume of the mixture was reducedto 750 mL in vacuo, then the residual liquid was diluted with 2 L ofether. The mixture was filtered and the filtrate concentrated. Theresidue was triturated with hot hexane, and the combined hexane extractswere concentrated to give 62.8 g (54%) of the title compound: ¹ H NMR(DMSO-d₆ 300 MHz) δ 9.14 (m, 2H).

126b. 5-Amino-3-bromo-2-fluoropyridine

To a solution of 3-bromo-2-fluoro-5-nitropyridine from Step 126a above(5.0 g, 23 mmol) in MeOH (100 mL) was added tin(II) chloride dihydrate.The mixture was heated at reflux for 3 hours, then cooled to ambienttemperature and concentrated in vacuo. The residue was diluted withsaturated aqueous NaHCO₃ and EtOAc resulting in formation of an emulsionwhich was filtered. The filtrate was poured into a separatory funnel andthe layers were separated. The aqueous phase was extracted with EtOAc.The combined organic extracts were washed with brine, dried (MgSO₄), andconcentrated. Purification by chromatography (silica gel; hexane/EtOAc,70:30) afforded 3.61 g (83%) of the title compound as a yellow solid: mp91-92° C.; ¹ H NMR (CDCl₃, 300 MHz) δ 7.15 (dd, J=2.5, 7.5 Hz, 1H), (dd,J=2.0, 2.5 Hz, 1H); MS (DCI/NH₃) m/z 191, 193 (M+H)⁺ 208, 210 (M+NH₄)⁺.

126c. 5-Amino-2-fluoro-3-vinylpyridine

To a stirred solution of 5-amino-2-fluoro-3-bromopyridine from step 126babove (3.25 g, 17.0 mmol) in toluene (20 mL) was addedtributyl(vinyl)tin (Aldrich, 7.64 g, 20.4 mmol) followed bytetrakis(triphenylphosphine) palladium (Aldrich, 0.63 g, 1.7 mmol). Thereaction mixture was heated at 100° C. for 24 h. The solvent was removedin vacuo and the residue was purified by column chromatography (silicagel; EtOAc/hexane, 4:6) to afford the desired material as beige solids(2.30 g, 98%): ¹ H NMR (CDCl₃, 300 MHz) δ 3.61 (br s, 2H), 5.44 (d,J=11.5 Hz, 1H), 5.83 (d, J=17.5 Hz, 1H), 6.66 (m, 1H), 7.18 (dd, J=3.0Hz, 5.0 Hz, 1H), 7.52 (m, 1H); MS (CI/NH₃) m/z 139 (M+H)⁺, 156 (M+NH₄)⁺.

126d. 5-Amino-3-ethyl-2-fluoropyridine

A solution of the 5-amino-2-fluoro-3-vinylpyridine from Step 126c above(2.30 g, 16.6 mmol) in MeOH (50 mL) was added to a suspension of 10%palladium on activated carbon (Aldrich, 0.10 g) in MeOH (75 ml). Themixture was placed under an atmosphere of H₂ (balloon) for 48 h. Thecatalyst was removed by filtration and the solvent was evaporated toyield the title compound as a beige solid (2.31 g, 99%): ¹ H NMR (CDCl₃,300 MHz) δ 1.22 (t, J=7.5 Hz, 3H), 2.58 (q, J=7.5 Hz, 2H), 6.96 (dd,J=3.0, 5.1 Hz, 1H), 7.45 (m, 1H); MS (CI/NH₃) m/z 141 (M+H)⁺, 158(M+NH₄)⁺.

126e. 5-Acetoxy-3-ethyl-2-fluoropyridine

To a stirred solution of the 5-amino-3-ethyl-2-fluoropyridine from Step126d above (2.30 g, 16.4 mmol) in 3:1 dimethoxyethane:CH₂ Cl₂ (50 mL) at-10° C. was slowly added borontrifluoride etherate (Aldrich, 4.23 mL,34.5 mmol). t-Butylnitrite (Aldrich, 2.34 mL, 19.7 mmol) was added overthe course of 15 min., keeping the reaction temperature below -5° C. Thereaction mixture was warmed to 0° C. and stirred for 30 minutes. Pentane(500 mL) was added and the solid tetrafluoroborate diazonium salt wascollected by filtration. The diazonium salt was dissolved in aceticanhydride (40 mL) and heated at 95° C. for 2 h (N₂ evolution was notedat 85° C.). The solvent was evaporated, the residue was dissolved in Et₂O (250 mL), and washed with saturated aqueous NaHCO₃ (2×150 mL). Thecombined aqueous phases were extracted with Et₂ O (2×150 mL). Thecombined organic phases were washed with brine (50 mL), dried (MgSO₄),and concentrated. The crude product was purified by columnchromatography (silica gel; EtOAc/hexane, 4:6) to afford the titlecompound as a yellow oil (2.22 g, 74%): ¹ H NMR (CDCl₃, 300 MHz) δ 1.26(t, J=7.5 Hz, 3H), 2.32 (s, 3H), 2.67 (q, J=7.0 Hz, 2H), 7.35 (dd,J=2.5, 8.0 Hz, 1H), 7.84 (m, 1H); MS (CI/NH₃) m/z 184 (M+H)⁺, 201(M+NH₄)⁺.

126f. 3-Ethyl-2-fluoro-5-hydroxypyridine

To a stirred solution of the 5-acetoxy-3-ethyl-2-fluoropyridine fromStep 126e above (2.22 g, 12.1 mmol) in MeOH (50 mL) was added K₂ CO₃(0.84 g, 6.10 mmol). The reaction mixture was allowed to stir at roomtemperature 24 h. The solvent was evaporated and the residue was dilutedwith Et₂ O (100 mL) and water (100 mL). The phases were separated andthe aqueous phase was neutralized (pH 7) by the addition of 1 N aqueousHCl, and extracted with diethyl ether (2×100 mL). The combined etherealextracts were washed with brine (50 mL), dried (MgSO₄), and the solventevaporated. The crude product was purified by column chromatography(silica gel; EtOAc/hexane, 4:6) to afford the desired material as anoff-white solid (1.18 g, 69%): ¹ H NMR (CDCl₃, 300 MHz) δ 1.24 (t, J=7.5Hz, 3H), 2.63 (q, J=7.5 Hz, 2H), 7.24 (dd, J=2.0, 5.0 Hz, 1H), 7.62 (m,1H); MS (CI/NH₃) m/z 142 (M+H)⁺, 159 (M+NH₄)⁺.

126g.5-(1-tert-Butyloxy-(2S)-azetidinylmethoxy)-3-ethyl-2-fluoropyridine

To a solution of 3-ethyl-2-fluoro-5-hydroxypyridine from example 126f(0.53 g, 3.8 mmol) in DMF (10 mL) was added powdered potassium hydroxide(J T Baker, 0.34 g, 6.1 mmol) and the reaction mixture was stirred atroom temperature for 1.5 hour until the KOH was dissolved.(S)-1-(tert-Butyloxycarbonyl)-2-para-toluenesulfonyloxymethyl)azetidinefrom Example 10c (1.28 g, 3.8 mmol) was then added and the reactionmixture was heated at 80° C. for 18 h. After cooling to ambienttemperature the solution was diluted with water (50 mL) and extractedwith EtOAc (3×30 mL). The combined organic extracts were washed withbrine (25 ml), dried (MgSO₄), and the solvent was removed in vacuo. Thecrude reaction product was purified by column chromatography (silicagel; EtOAc/hexane, 3:7) to afford the title compound as a yellow oil(0.93 g, 79%): ¹ H NMR (CDCl₃, 300 MHz) δ 1.23 (t, J=7.7 Hz, 3H), 1.42(s, 9H), 2.33 (m, 1H), 2.62 (q, J=7.7 Hz, 2H), 3.90 (m, 2H), 4.11 (dd,J=3.0, 7.0 Hz, 2H), 4.29 (m, 1H), 4.51 (m, 1H), 7.25 (m, 1H), 7.68 (m,1H); MS (CI/NH₃) m/z 311 (M+H)⁺, 328 (M+NH₄)⁺.

126h. 5-((2S)-Azetidinylmethoxy)-3-ethyl-2-fluoropyridine tosylate

A solution of the coupled product from Step 126g above (0.93 g, 3.0mmol) was dissolved in dry CH₂ Cl₂ (10 mL), and cooled to 0° C.Trifluoroacetic acid (Aldrich, 10 mL) was added, and the solution wasallowed to stir at 0° C. for 1 hour. The reaction mixture was carefullypoured into saturated aqueous NaHCO₃ (50 mL), and extracted with EtOAc(3×30 mL). The combined organic extracts were washed with brine (25 mL),dried (MgSO₄), and the solvent was evaporated. The crude product waspurified by column chromatography (silica gel; MeOH/CH₂ Cl₂, 1:9, thenCHCl₃ /MeOH/NH₄ OH, 80:20:1) to afford the free base of the titlecompound as a yellow oil (0.22 g, 35%). The oil was dissolved in EtOH,cooled to 0° C., and p-toluenesulfonic acid monohydrate (Aldrich, 0.20g, 1.0 mmol) was added. After stirring at 0° C. for 30 minutes, thesolvent was evaporated and the residue was triturated from Et₂ O toafford an off-white solid (0.27 g, 24% from isolated free amine): mp106-108° C; [αC]D²¹ -20.4 (c 0.6, CH₂ Cl₂) free base; ¹ H NMR (DMSO-d₆)δ 1.18 (t, 3H, J=7.5 Hz), 2.28 (s, 3H), 2.39 (m, 1H), 2.50 (m, 1H), 2.61(q, 2H, J=7 Hz), 3.85 (m, 1H), 3.95 (m, 1H), 4.37 (m, 2H), 4.70 (m, 1H),7.10 (d, 2H, J=7.5 Hz), 7.47 (d, 2H, J=7.5 Hz), 7.54 (dd, 1H, J=3,5 Hz),7.78 (m, 1H), 8.83 (br s, 2H); MS (CI/NH₃) m/z 211 (M+H)⁺, 228 (M+NH₄)⁺.Anal. Calcd for C₁₁ H₁₅ FN₂ O.1.5 TsOH: C, 55.11; H, 5.81; N, 6.24.Found: C, 54.94; H, 5.86; N, 6.23.

Example 127 2-Chloro-3-methyl-5-(2-(R)-azetidinylmethoxy)pyridinecitrate

Following the procedure of Example 25 Steps a and b, except substituting(R)-1-t-butyloxycarbonyl-2-azetidinemethanol for the(S)-1-t-butyloxycarbonyl-2-azetidinemethanol thereof, the title compoundwas prepared: mp 104-106° C.; [α]_(D) ²⁵ +10.3 (c 0.3, MeOH); MS(DCI/NH₃) m/z: 213 (M+H)⁺ ; ¹ H NMR (D₂ O, 300 MHz) δ: 2.27 (d, J=10.5Hz, 1H), 2.37 (s, 3H), 2.41-2.91 (m, 8H), 4.08-4.13 (m, 2H), 4.40 (d,J=4 Hz, 1H), 4.93 (m, 1H), 7.49 (d, J=3.1 Hz, 1H), 7.97 (d, J=3.0 Hz,1H); Anal. Calcd for C₁₀ H₁₃ N₂ OCl.C₆ H₈ O₇ : C, 47.45; H, 5.19; N,6.92. Found: C, 47.16; H, 5.48; N, 7.08.

Example 128 5-(2-(R)-azetidinylmethoxy)-2-bromo-pyridine tosylate

128a. 5-amino-2-bromopyridine

A mixture of 2-bromo-5-nitropyridine (Aldrich, 30.75 g, 151.5 mmol),water (250 mL), and acetic acid (110 mL) was heated to 45° C. Ironpowder (24.5 g, 439 mmol) was added at a rate which kept the temperaturebelow 53° C., then the mixture was stirred at 48° C.±5° C. The mixturewas cooled to room temperature and filtered through diatomaceous earth.The filter cake was washed with ethyl acetate, and the aqueous mixturewas extracted with ethyl acetate. The combined organic fractions werewashed with saturated Na₂ CO₃ and brine, dried over MgSO₄, and thesolvent was removed in vacuo. The residue was chromatographed on silicagel, eluting with 100:0 to 50:50 hexane:ethyl acetate to give 20.4 g ofthe title compound: ¹ H NMR (CDCl₃ 300 MHz) δ 6.88 (dd, 1H, J=8.5, 2.4Hz) 7.22 (d, 1H, J=8.2 Hz) 7.85 (d, 1H, J=3 Hz); MS (CI/NH₃) m/z: 173(M+H)⁺, 190 (M+NH₄)⁺.

128b. 5-acetoxy-2-bromopyridine

To 25.6 mL of boron trifluoride etherate (208 mmol, Aldrich) cooled to-15° C. under N₂ was added 18 g (104 mmol) of 5-amino-2-bromopyridinefrom step 128a above dissolved in 35 mL of DME. Then tert-butyl nitrite(14.7 mL, 125 mmol, Aldrich) was added at a rate which kept thetemperature below 0° C. DME (65 mL) and methylene chloride (60 mL) werethen added. After 10 minutes at -10° C. the mixture was warmed to 5° C.and stirred for 30 min. Pentane (400 mL) was then added to the reactionmixture, the solid was collected by suction filtration, washed with coldether, air dried, and dissolved in 125 mL acetic anhydride. Theresulting solution was heated to 100° C.±5° C. for 1 hour. The solventwas removed in vacuo, and the residue was suspended in saturated aqueousNa₂ CO₃, and extracted with ethyl ether. The ether solution was driedover MgSO₄, the solvent was removed in vacuo, and the residue waschromatographed on silica gel, eluting with 100:0 to 60:40 hexane:ethylacetate to give 13.6 g of the title compound: ¹ H NMR (CDCl₃, 300 MHz) δ2.35 (s, 3H) 7.37 (dd, 1H), 7.51 (d, 1H), 8.19-8.21 (d, 1H) MS m/z: 216(M+H)⁺, 233 (M+NH₄)⁺.

128c. 2-bromo-5-hydroxypyridine

5-Acetoxy-2-bromopyridine (12.8 g, 60 mmol) from step 128b above wasdissolved in 15% aqueous NaOH (50 mL) at 0° C., and the solution waswarmed to room temperature and stirred for 60 minutes. After completeconsumption of the starting material the solution was neutralized byaddition of 1 N HCl. The aqueous mixture was extracted with ethylacetate (3×200 mL). The organic extracts were washed with brine (4×50nL), water (2×50 mL), dried (MgSO₄), and the solvent was evaporated toyield 9.8 g of the title compound: ¹ H NMR (CDCl₃, 300 MHz) δ 7.14 (dd,1H, J=3.2 Hz),7.37 (d, 1H, J=8.5 Hz), 8.04 (d, 1H, J=2.4 Hz) MS (CI/NH₃)m/z: 174 (M+H)⁺.

128d. 5-(2-(1-Boc-(R)-azetidinylmethoxy)-2-bromopyridine

2-Bromo-5-hydroxypyridine from step 128c above (0.130g, 0.75mmol) andBoc-(R)-(toluensulfonyloxymethyl)azetidine (0.255 g, 0.75 mmol) fromExample 1 were allowed to react under the conditions of Example 1 toafford a colorless oil (0.208 g, 81.3% yield). ¹ H NMR (CDCl₃, 300 MHz)δ 1.41 (s, 9H), 2.20-2.42 (m, 2H, obscured by solvent ), 3.88 (t, 2H,J=7.5 Hz), 4.11 (dd, 1H, J=2.9, 10.0 Hz), 4.32 (m, 1H), 4.50 (m, 1H),7.16 (dd, 1H, J=3.2, 8.7 Hz), 7.37 (d, 1H, J=8.8 Hz), 8.11 (d, 1H, J=3.8Hz); MS (CI/NH₃); m/z 343 (M+H)⁺, 360 (M+NH₄)⁺.

128e. 5-(2-(R)-azetidinylmethoxy)-2-bromopyridine tosylate

The product of step 128d (0.17 g, 0.52 mmol) was dissolved indichloromethane (5.6 mL) and cooled to 0° C. Trifluoroacetic acid (1.4mL) was then added and the mixture was stirred for two hours at 0° C.The solvents were removed under reduced pressure and the residue wastaken up in brine (25 mL) and extracted with a 3:1 mixture ofchloroform/isopropanol (3×20 mL). The combined organic extracts werewashed with brine, dried over sodium sulfate and concentrated to leavethe free base as a colorless oil (0.127 g, 100% yield). The free base(0.123 g, 0.506 mmol was dissolved in ethanol (10 mL), cooled to 0° C.,and treated with p-toluenesulfonic acid (0.096 g, 0.505 mmol). Afterstirring for 30 minutes at 0° C., the ethanol was removed to give thetitle compound as a white solid (0.209 g, 100% yield). mp 174-176°;[α]²⁵ ^(D) +5.2 (c 0.9, MeOH); ¹ H NMR (DMSO, 300 MHz) δ 2.29 (s, 3H),2.34-2.59 (m, 2H), 3.82-4.04 (m, 2H), 4.29-4.46 (m, 2H), 4.74 (m, 1H),7.11 (d, 2H, J=8.1 Hz), 7.42-7.51 (m, 3H), 7.61 (d, 1H, J=8.9 Hz), 8.19(d, 1H, J=3.4 Hz), 8.79-8.96 (bs, ¹ H); MS (CI/NH₃); m/z 243 (M+H)⁺, 260(M+NH₄)⁺. Anal. Calcd for C₉ H₁₁ BrN₂ O.TsOH: C, 46.27; H, 4.61; N,6.75. Found: C, 46.65; H, 4.63; N, 6.37.

Example 129 5-((2R)-Azetidinylmethoxy)-2-fluoro-3-vinylpyridine tosylate

129a. 5-(1-Boc-2-(R)-azetidinylmethoxy)-3-ethenyl-2-fluoropyridine

Following the procedures of Example 131 below, replacing(S)-1-(tert-butyloxycarbonyl)-2-para-toluenesulfonyloxymethyl)azetidinethereof with its enantiomer(R-1-(tert-butyloxycarbonyl)-2-para-toluenesulfonyloxymethyl)azetidinefrom Example 1 above, the title compound was prepared as a clear oil in76% yield: ¹ H NMR (CDCl₃, 300 MHz) δ 1.42 (s, 9H), 2.24-2.42 (m, 2H),3.92 (m, 1H), 4.13 (dd, J=3.0, 7.0 Hz, 2H), 4.35 (m, 1H), 4.54 (m, 1H),5.49 (d, J=11.0 Hz, 1H), 5.89 (d, J=18.0 Hz, 1H), 6.75 (m, 1H), 7.47(dd, J=2.7, 5.1 Hz, 11H), 7.76 (m, 1H); MS (CI/NH₃) m/z 309 (M+H)⁺, 326(M+NH₄)⁺.

129b. 5-(2-(R)-Azetidinylmethoxy)-3-ethenyl-2-fluoropyridine tosylat

To a solution of the product from step 129a above (0.21 g, 0.7 mmol) inmethylene chloride (10 mL) at 0° C. was added trifluoroacetic acid (10mL). After stirring for 1 hour at 0° C., the volatile components wereremoved in vacuo. The residue was diluted with saturated aqueous NaHCO₃and extracted with EtOAc (3×). The combined organic extracts were washedwith brine, dried (MgSO₄), and concentrated. The residue was purified bycolumn chromatography (silica gel; MeOH/CH₂ Cl₂, 1:9, then CHCl₃NMeOH/NH₄ OH, 80:20:1) to afford the desired material as a yellow oil(0.10 g, 68%). The oil was dissolved in EtOH, cooled to 0° C., andp-toluenesulfonic acid monohydrate (0.09 g, 0.5 mmol) was added. Afterstirring at 0° C. for 30 minutes, the solvent was evaporated and thesolid was triturated with Et₂ O to afford the title compound as a lightyellow solid (0.05 g, 20% from isolated free amine): mp 84-85° C.;[α]_(D) ²³ +12.6 (c 0.5, MeOH); ¹ H NMR (DMSO-d₆, 300 MHz) δ 2.28 (s,3H), 2.40 (m, 1H), 2.51 (m, 1H), 3.86-4.02 (br m, 2H), 4.38 (m, 2H),4.74 (m, 1H), 5.60 (d, J=11.0 Hz, 1H), 6.09 (d, J=17.5 Hz, 1H), 6.75 (m,1H), 7.11 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.86 (m, 2H), 8.85(br s, 2H); MS (CI/NH₃) m/z 209 (M+H)⁺, 226 (M+NH₄)⁺. Anal. Calcd forC₁₁ H₁₃ FN₂ O.TsOH.0.3 H₂ O: C, 56.03; H, 5.64; N, 7.26. Found: C,55.87; H, 5.43; N, 7.20.

Example 130 3-(2-(S)-azetidinylmethoxy)-5-(3-propenyl)pyridinehydrochloride

130a. 3-(1-Boc-2-(S)-azetidinylmethoxy)-5-(3-propenyl)pyridine

3-(1-Boc-2-(S)-azetidinylmethoxy)-5-bromopyridine (0.95 g, 2.77 mmol,from Example 12 Step a) in toluene (10 mL) was addedtetrakis(triphenylphosphine)palladium (100 mg) and allyltributyltin(1.72 mL, 5.54 mmol). The mixture was stirred and refluxed for two days.Solvent was evaporated and the residue was chromatographed (silica gel;hexane/EtOAc, 5:1 to 1:1) to afford an oil (250 mg, 30%): ¹ H NMR(CDCl₃, 300 MHz) δ 1.42 (s, 9H), 2.22-2.42 (m, 2H), 3.37 (d, 2H, J=7.0Hz), 3.87-3.92 (m, 2H), 4.16 (m, 1H), 4.30 (m, 1H), 4.50 (m, 1H),5.07-5.17 (m, 2H), 5.9 (m, 1H), 7.07 (m, 1H), 8.08 (m, 1H), 8.19 (d, 1H,J=3.0 Hz); MS (CI/NH₃) m/z 305 (M+H)⁺.

130b. 3-(2-(S)-azetidinylmethoxy)-5-(3-propenyl)pyridine

The product from step 130a above (250 mg, 0.82 mmol) in CH₂ Cl₂ (2 mL)was cooled to 0° C., TFA (1.11 mL) was then added carefully. Thereaction mixture was stirred at 0° C. for 40 min. The mixture was thenwarmed to room temperature and kept stirring for 30 min. Afterneutralization with aqueous 10% NaOH, the reaction mixture was extractedwith CH₂ Cl₂ (3×). The combined organic layers were dried (MgSO₄),concentrated and chromatographed (silica gel; CH₂ Cl₂ /MeOH/NH₄ OH,10:0.3:0 to 10:1:0.03) to afford a light yellow oil (365 mg, 69%): ¹ HNMR (CDCl₃, 300 MHz) δ 2.28 (m, 1H), 2.42 (m, 1H), 3.37 (d, 2H, J=6.5Hz), 3.52 (m, 1H), 3.76 (m, 1H), 4.04 (m, 2H), 4.30 (m, 1H), 5.06-5.16(m, 2H), 5.94 (m, 1H), 7.04 (m, 1H), 8.08 (d, 1H, J=2.0 Hz), 8.18 (d,1H, J=3.0 Hz); MS (CI/NH₃) m/z 239 (M+H)⁺.

130c. 3-(2-(S)-azetidinylmethoxy)-5-(3-propenyl)pyridine hydrochloride

To the product of step 130b above in Et₂ O was added hydrogen chloride(1.0 M in Et₂ O) carefully to afford the tittle compound: ¹ H NMR (D₂ O)δ 2.70 (q, 2H, J=8.5 Hz), 3.49 (d, 2H, J=6.5 Hz), 4.02-4.20 (m, 2H),4.44 (d, 2H, J=4.5 Hz), 4.95 (m, 1H), 5.12-5.20 (m, 2H), 6.05 (m, 1H),7.53 (s, 1H), 8.15 (s, 1H), 8.24 (d, 1H, J=2.0 Hz); MS (CI/NH₃) m/z 205(M+H)⁺. Anal. Calcd for C₁₂ H₁₆ N₂ O.₂ HCl.0.2 H₂ O: C, 54.14; H, 6.82;N, 10.52. Found: C, 54.30; H, 6.82; N, 10.49. [α]²⁵ _(D) -3.5 (c 0.63,MeOH).

Example 131 5-(2-(S)-Azetidinylmethoxy)-3-ethenyl-2-fluoropyridinetosylate

131a. 3-Bromo-2-fluoro-5-nitropyridine

3-Bromo-2-chloro-5-nitropyridine (119 g, 0.500 mol, prepared accordingto V. Koch and S. Schnatterer, Synthesis, 1990, 497-498), potassiumfluoride (79.5 g, 1.37 mol), and tetraphenylphosphonium bromide (109 g,0.260 mol) were combined in acetonitrile (1.5 L) and heated at refluxfor 4 days until GLC indicated complete consumption of the3-bromo-2-chloro-5-nitropyridine. The volume of the mixture was reducedto 750 mL in vacuo then and diluted with 2 L of ether. The mixture wasfiltered and the filtrate concentrated. The residue was triturated withhot hexane (2×1 L then 2×0.5 L) and the combined hexane extracts wereconcentrated to give 62.8 g (54%) of the title compound: ¹ H NMR(DMSO-d₆ 300 MHz) δ 9.14 (m, 2H).

131b. 5-Amino-3-bromo-2-fluoropyridine

To a solution of 3-bromo-2-fluoro-5-nitropyridine from step 131a above(5.0 g, 23 mmol) in MeOH (100 mL) was added tin(II) chloride dihydrate.The mixture was heated at reflux for 3 hours, then cooled to ambienttemperature and concentrated in vacuo. The residue was diluted withsaturated aqueous NaHCO₃ and EtOAc resulting in formation of an emulsionwhich was filtered. The filtrate was poured into a separatory funnel andthe layers were separated. The aqueous phase was extracted with EtOAc(2×). The combined organic extracts were washed with brine, dried(MgSO₄), and concentrated. Purification by chromatography (silica gel;hexane/EtOAc, 70:30) afforded 3.61 g (83%) of the title compound as ayellow solid: mp 91-92° C.; ¹ H NMR (CDCl₃, 300 MHz) δ 7.15 (dd, J=2.5,7.5 Hz, 1H), (dd, J=2.0, 2.5 Hz, 1H); MS (CI/NH₃) m/z 191, 193 (M+H)⁺208, 210 (M+NH₄)⁺.

131c. 5-Amino-3-ethenyl-2-fluoropyridine

To a stirred solution of 5-amino-3-bromo-2-fluoropyridine (3.25 g, 17.0mmol) from step 131b above in toluene (20 mL) was addedtributyl(vinyl)tin (7.64 g, 20.4 mmol) followed bytetrakis(triphenylphosphine) palladium (Aldrich, 0.63 g, 1.7 mmol). Thereaction mixture was heated at 100° C. for 24 h. The solvent was removedin vacuo and the residue was purified by column chromatography (silicagel; EtOAc/hexane, 4:6) to afford the title compound as a beige solid(2.30 g, 98%): ¹ H NMR (CDCl₃, 300 MHz) δ 3.61 (br s, 2H), 5.44 (d,J=11.5 Hz, 1H), 5.83 (d, J=17.5 Hz, 1H), 6.66 (m, 1H), 7.18 (dd, J=3.0,5.0 Hz, 1H), 7.52 (m, 1H); MS (CI/NH₃) m/z 139 (M+H)⁺, 156 (M+NH₄)⁺.

131d. 5-Acetoxy-3-ethenyl-2-fluoropyridine

To a solution of the product from step 131c above (3.00 g, 21.7 mmol) in3:1 dimethoxyethane:CH₂ Cl₂ (50 mL) at -10° C. was slowly addedborontrifluoride etherate (Aldrich, 5.60 mL, 45.6 mmol). t-Butylnitrite(Aldrich, 3.10 mL, 26.0 mmol) was added over the course of 15 minutes,maintaining the reaction temperature below -5° C. The reaction mixturewas warmed to 0° C. and stirred for 30 minutes. Pentane (500 mL) wasadded and the solid tetrafluoroborate diazonium salt was collected byfiltration. The diazonium salt was dissolved in acetic anhydride (40 mL)and heated at 95° C. for 2 hours (N₂ evolution was noted ˜85° C.). Aftercooling to ambient temperature, the dark mixture was concentrated invacuo. The residue was diluted with saturated aqueous NaHCO₃ andextracted with Et₂ O (3×150 mL). The combined organic extracts werewashed with brine (50 mL), dried (MgSO₄), and concentrated. The crudeproduct was purified by column chromatography (silica gel; EtOAc/hexane,40:60) to afford the title compound as a yellow oil (1.51 g, 40%): ¹ HNMR (CDCl₃, 300 MHz) δ 2.35 (s, 3H), 5.54 (d, J=11.0 Hz, 1H), 5.90 (d,J=18.0 Hz, 2H), 6.75 (mn, 1H), 7.66 (dd, J=2.0, 5.0 Hz, 1H); MS (CI/NH₃)m/z 182 (M+H)⁺, 199 (M+NH₄)⁺.

131e. 3-Ethenyl-2-fluoro-5-hydroxypyridine

To a stirred solution of the the product from step 131d above (1.40 g,7.70 nmmol) in MeOH (50 mL) was added K₂ CO₃ (0.53 g, 3.9 mmol). Afterstirring at room temperature 24 hours, the solvent was evaporated andthe residue was diluted with Et₂ O (100 mL) and water (100 mL). Thephases were separated and the aqueous phase was neutralized (pH=7) bythe addition of 1 N aqueous HCl, and extracted with diethyl ether (2×100mL). The combined ethereal extracts were washed with brine (50 mL),dried (MgSO₄), and concentrated. The crude product was purified bycolumn chromatography (silica gel; EtOAc/hexane, 40:60) to afford thetitle compound as an off-white solid (0.81 g, 76%): ¹ H NMR (CDCl₃, 300MHz) δ 5.50 (d, J=11.0 Hz, 1H), 5.87 (d, J=17.5 Hz, 1H), 6.75 (m, 1H),7.72 (dd, J=3.0, 5.0 Hz, 1H), 7.69 (m, 1H); MS (CI/NH₃) m/z 140 (M+H)⁺,157 (M+NH₄)⁺.

131f. 5-(1-Boc-2-(S)-azetidinylmethoxy)-3-ethenyl-2-fluoropyridine

To the product from step 131e above (0.60 g, 4.3 mmol) in DMF (10 mL)was added powdered potassium hydroxide (0.36 g, 6.5 mmol) and thereaction mixture was stirred at room temperature for 1.5 h until the KOHwas dissolved. 1-Boc-2-(S)-azetidinemethyl-p-toluenesulfonate (1.96 g,4.3 mmol, from Example 10) was then added and the reaction mixture washeated at 80° C. for 18 h. The reaction mixture was diluted with water(50 mL) and extracted with EtOAc (3×30 mL). The combined organicextracts were washed with brine (25 ml), dried (MgSO₄), and the solventwas removed in vacuo. The crude reaction product was purified by columnchromatography (silica gel; CH₂ Cl₂ /MeOH, 98:2) to afford the desiredmaterial as a yellow oil (1.44 g, >100%): ¹ H NMR (CDCl₃, 300 MHz) δ1.42 (s, 9H), 2.45 (m, 2H), 3.90 (m, 1H), 4.13 (dd, J=3.0, 7.5 Hz, 2H),4.35 (m, 1H), 4.54 (m, 1H), 5.49 (d, J=11.0 Hz, 1H), 5.89 (d, J=17.5 Hz,1H), 6.74 (m, 1H), 7.47 (m, 1H), 7.76 (m, 1H); MS (CI/NH₃) m/z 309(M+H)⁺, 326 (M+NH₄)⁺.

131g. 5-(2-(S)-Azetidinylmethoxy)-3-ethenyl-2-fluoropyridine tosylate

To a solution of the coupled product from Step 131f above (1.44 g, 4.70mmol) in methylene chloride (10 mL) at 0° C. was added trifluoroaceticacid (10 mL). After stirring for 1 hour at 0° C., the volatilecomponents were removed in vacuo. The residue was diluted with saturatedaqueous NaHCO₃ and extracted with EtOAc (3×). The combined organicextracts were washed with brine, dried (MgSO₄), and concentrated. Theresidue was purified by column chromatography (silica gel; MeOH/CH₂ Cl₂,1:9, then CHCl₃ /MeOH/NH₄ OH, 80:20:1) to afford the desired material asa yellow oil (0.37 g, 41%): [α]_(D) ²⁵ -2.8 (c 0.4, MeOH). The oil wasdissolved in EtOH, cooled to 0° C., and p-toluenesulfonic acidmonohydrate (0.34 g, 1.8 mmol) was added. After stirring at 0° C. for 30minutes, the solvent was evaporated and the solid was triturated withEt₂ O to afford the title compound as a white solid (0.30 g, 48% fromisolated free amine): mp 251-253° C.; ¹ H NMR (DMSO-d₆, 300 MHz) δ 2.29(s, 3H), 2.38 (m, 1H), 2.43 (m, 1H), 3.86-4.02 (m, 2H), 4.40 (m, 2H),4.74 (m, 1H), 5.60 (d, J=11.0 Hz, 1H), 6.09 (d, J=16.5 Hz, 1H), 6.74 (m,1H), 7.11 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 7.87 (m, 2H), 8.86(br s, 2H); MS (CI/NH₃) m/z 209 (M+H)⁺, 226 (M+NH₄)⁺. Anal. Calcd forC₁₁ H₁₃ FN₂ O.1.3 TsOH: C, 55.87; H, 5.46; N, 6.48. Found: C, 56.23; H,5.68; N, 6.28.

Example 132 5-nitro-3-(2-(S)-azetidinylmethoxy)pyridine hydrochloride

132a. 3-benzyloxy-5-bromopyridine

NaH (60% in mineral oil) (40.9 g 1.0225 mol) in 800 mL of DMF was cooledto 0° C., and benzyl alcohol (105 mL 1.014 mol) was added slowly. Thereaction mixture was stirred for 1 hour at 20° C., then3,5-dibromopyridine (200.4 g, 846 mmol) was added and the mixture wasstirred for 16 hours. The mixture was quenched with saturated NH₄ Cl(500 mL), diluted with 400 mL water and extracted with Et₂ O (5×300 mL).The combined Et₂ O extracts were washed with 50% brine (6×300 mL) anddried (MgSO₄). The solvent was evaporated in vacuo and the crude productwas recrystallized from Et₂ O to afford 161 g (72%) of the titleproduct, mp 63-68° C. ¹ H NMR (CDCl₃, 300 MHz) δ 8.37-8.27 (m, 2H),7.5-7.35 (m, 6H), 5.1 (s, 1H). MS (DCI/NH₃) m/z 264, 266 (M+H)⁺.

132b. 3-amino-5-benzyloxypyridine

The product of Example 132a (41.3 g 156 mmol), copper(I) bromide (22.43g 156 mmol), MeOH (275 mL), and liquid NH₃ (50 mL) were combined in astainless steel reactor and heated to 130° C. for 24 hours. The mixturewas allowed to cool to ambient temperature, then concentrated. Theresidue was suspended in 300 mL of saturated aqueous Na₂ CO₃ andextracted with CH₂ Cl₂ (4×500 mL). The combined CH₂ Cl₂ extracts werewashed with brine, dried (MgSO₄), and concentrated. The crude productwas chromatographed (silica gel; hexane/EtOAc, 9:1 to 7:3) to afford15.6 g (50%) of the title compound. ¹ H NMR (CDCl₃, 300 MHz) δ 8.21-8.29(m, 2H), 7.44-1.26 (m, 6H), 5.10 (s, 2H). MS (DCI/NH₃) m/z 201 (M+H)⁺.

132c. 3-amino-5-hydroxypyridine

The product of Example 132b (15.47 g, 77.25 mmol) in MeOH (25 mL) wasstirred under an atmosphere of H₂ in the presence of 5% Pd/C (100 mg)for 48 hours. The mixture was filtered and concentrated, then the crudeproduct was chromatographed (silica gel; CHCl₃ /MeOH, 9:1) to afford 4.5g (53%) of the title compound MS (DCI/NH₃) m/z 111 (M+H)⁺, 128 (M+NH₄)⁺.¹ H NMR (CDCl₃, 300 MHz) δ 7.4 (d, J=3 Hz, 1H), 7.3 (d, J=2.5 Hz, 1H),6.33 (dd, J=2.6 Hz, 1H).

132d. 3-hydroxy-5-nitropyridine

Potassium persulfate (56.8 g 210 mmol) was ground into 31.5 mL of concdsulfuric acid, and the solution was added to a solution of the productof Example 132c (2.75 g 25 mmol) in concd sulfuric acid (27 mL). Themixture was allowed to stand for 72 hours, then was poured over ice andadjusted to pH 6 with concd NH₄ OH. The solution was extracted withEtOAc (4×100 mL), then the EtOAc extracts were dried (MgSO₄) andconcentrated. The crude product was chromatographed (silica gel; CHCl₃/MeOH, 99:1 to 9:1) to afford 1.65 g (47%) of the title compound. ¹ HNMR (CDCl₃, 300 MHz) δ 8.81(d, J=3 Hz, 1H), 8.51 (d, H=3 Hz, 1H), 7.82(dd, J=2.5 Hz, 1H). MS (DCI/NH₃) m/z 141 (M+H)⁺, 158 (M+NH₄)⁺.

132e. 5-nitro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine

1-BOC-2-(S)-azetidinylmethanol (868 mg, 4.64 mmol) and3-hydroxy-5-nitropyridine from Example 132d (500 mg, 3.57 mmol) werecoupled according the procedure of Example 17a. Solvent was removed, andthe residue was chromatographed (silica gel, hexane/ethyl acetate, 5:1)to afford the title compound (800 mg, 73%). ¹ H NMR (CHCl₃, 300 MHz) δ1.45 (s, 9H), 2.56 (m, 2H), 4.52 (m, 4H), 4.82 (m, 1H), 8.25 (t, J=3 Hz,1H), 8.65 (d, J=3 Hz, 1H), 9.05 (d, J=3 Hz, 1H). MS (DCI/NH₃) m/z 310(M+H)⁺.

132f. 5-nitro-3-(2-(S-azetidinylmethoxy)pyridine hydrochloride

To the product of Example 132e (800 mg, 2.58 mmol) in methylene chlorideat 0° C. was added HCl/Et₂ O and the solution was stirred for 1 hour.Solvent was removed and the residue was recrystallized from EtOH/Et₂ Oto afford the title compound (750 mg): mp 162-164° C. (dec). ¹ H NMR (D₂O, 300 MHz) δ 2.45 (m, 2H), 4.62 (m, 4H), 4.96 (m, 1H), 8.26 (t, J=3 Hz,1H), 8.75 (d, J=3 Hz, 1H), 9.25 (d, J=3 Hz, 1H). MS (APCI) m/z 210(M+H)⁺. Anal. Calcd. for C₉ H₁₂ ClN₃ O₃ O.0.30 HCl: C, 42.13; H, 4.83;N, 16.38. Found: C, 42.28; H, 4.87; N, 16.24.

The examples listed above and those within the scope of formula I withthe variables as recited herein are useful in the prevention ortreatment of pain with certain exceptions as identified herein. Thecompounds are also useful in the treatment of neuronal cell death and inthe treatment of inflammation. Applicants are also claiming those (S)compounds and those (R) compounds which have not been previously claimedor disclosed.

We claim:
 1. A method of treating or controlling pain humans, comprisingadministering to a patient in need of treatment thereof a compound offormula IA: ##STR15## or a pharmaceutically acceptable salt thereof,wherein Z, Y, X and the 2-azetidine stereochemistry are, respectively,selected from the group consisting of:H, H, CN (S); H, H, Cl (S); H, H,Cl (R); H, H, Br (R); H, H, F (S); H, H, F (R); H, H, CHF₂ (S); H, H,OMe (R); H, Me, Cl (S); H, Me, Cl (R); H, Et, F (S); H, ethenyl, Cl (S);H, ethenyl, Cl (R); H, ethenyl, F (S); H, ethenyl, F (R); H, ethynyl, Cl(S); H, ethynyl, Cl (R); H, Cl, Cl (S); H, Cl, Cl (R); H, Cl, F (S); H,Br, Me (S); H, Br, Me (R); H, Br, Cl (S); H, Br, Cl (R); H, Br, F (S);H, Br, F (R); H, n-Pr, H (S); H, ethenyl, H (S); H, ethenyl, H (R); H,3-propenyl, H (S); H, Cl, H (R); H, F, H (S); H, NO₂, H (S); H, OEt, H(S); Cl, H, H (S); Cl, H, H (R); F, H, H (S); F, H, F (S); F, H, Me (S);and F, H, Me (R).
 2. The method of treating or controlling pain in apatient in need of treatment thereof according to claim 1, wherein thecompound is selected from the group consisting of the (S) enantiomers.3. The method of treating or controlling pain in a patient in need oftreatment thereof according to claim 1, wherein the compound is selectedfrom the group consisting of the (R) enantiomers.
 4. The method oftreating or controlling pain in a patient in need of treatment thereofaccording to claim 1, wherein Z is H, Y is H and X is selected from thegroup consisting of Cl and F.
 5. The method of treating or controllingpain in a patient in need of treatment thereof according to claim 4,wherein the compound is 5-((2R)-azetidinylmethoxy)-2-chloropyridine or apharmaceutically acceptable salt thereof.
 6. The method of treating orcontrolling pain in a patient in need of treatment thereof according toclaim 4, wherein the compound is5-((2R)-azetidinylmethyloxy)-2-fluoropyridine or a pharmaceuticallyacceptable salt thereof.